No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics
Abstract
At the time of writing this commentary (February 2020), the coronavirus COVID‐19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS‐CoV‐2 virus may take many months. Moreover, vaccines based on viral‐encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS‐CoV‐2 virus infections. This idea is based on observations that the angiotensin‐converting enzyme 2 (ACE2) very likely serves as the binding site for SARS‐CoV‐2, the strain implicated in the current COVID‐19 epidemic, similarly to strain SARS‐CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS‐CoV‐2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.
... De esta forma a la vez que se produce la fijación del virus a la célula también inactiva el sistema ACE2/angiotensina (1-7)/Mas con lo que se potencia la acción de la angiotensina II y esto determina las lesiones tisulares varias .El receptor ACE2 está en la membrana celular unida a la calmodulina. La melatonina bloquea a la calmodulina con lo que el receptor se suelta de la membrana y deja de ser capaz de facilitarle la entrada al virus (29,30). ...
... La melatonina podría considerarse pues como un inhibidor indirecto del acoplamiento entre ACE2 y -SARS-COV-2 durante el proceso de la infección ( 30,31)bloqueando la calmodulina ( 31 32,33) que mantiene el ACE2 en la membrana ( 34) con lo que conseguimos una reducción importante de la carga viral ( 25) También hay un estudio reciente que informa del importante papel que juega el receptor del Factor de crecimiento epidérmico (EGF) en el proceso de replicación del virus SARS-CoV-2 en las células infectadas (35) , de manera que el bloqueo de dicha interacción impide la replicación del virus hasta que el punto de haberse convertido en una diana terapéutica importante. La melatonina ha demostrado poder interferir eficazmente en la vía EGF para bloquear la acción infectiva (36). ...
Melatonin is a hormone that acts facilitating the appearance of physiological sleep It has also a very evident antinflammatory and antioxidant capacities that result in beneficial actions on the aging processes in the cardiovascular system and in the lungs where our group has detected a protective action against oxidative stress , inflammation and apoptosis . Although melatonin is not viricidal by itself in some models of viral infections it has demonstrated its ability to reduce viral load and also inflammation and oxidation, reducing the severity of the disease. In COVID 19 melatonin has been shown to be able to interfere with the infectious process that takes place through ACE2 and EGF receptors being able to block these interactions thus reducing viremia .It is able to block the activation of the NLRP3 inflammasome thus dramatically reducing the massive secretion of cytokines and markedly reducing hyperinflammation and apoptosis leading to a better evolution of the disease .For all these reasons melatonin could play an important role in the treatment of COVID 19.
... Probiotic strains improve mucosal immunity and can help improve gut and lung barrier and homeostasis by increasing regulatory T cells, improving antiviral defenses, and reducing proinflammatory cytokines in respiratory infections such as COVID-19 (61). ACE inhibitory effect of probiotics SARS-CoV-2 is invaded by the host cell by binding to surface spike proteins to the angiotensin-converting enzyme (ACE2) receptor and is produced and amplified by the serine proteinase TMPRSS2 (88,89). On the other hand, the mechanism of acute lung injury is also triggered by the activation of the reninangiotensin system (RAS), in which ACE2 has a protective effect. ...
The new viral pandemic of COVID-19 is caused by the new coronavirus (SARS-CoV-2), which has plunged the world into an economic and health crisis. The lack of specific treatment strategies is necessary to prevent the spread of infection caused by such a previously unknown viral agent. Evidence suggests that COVID-19 disease is associated with intestinal dysbiosis. Probiotics are living microbes that benefit human health by changing the composition of intestinal microbiota. The close relationship between the gastrointestinal tract and the respiratory tract indicates the influence of one on the function of the other. Emerging studies show the ability of probiotics to regulate immune responses in the respiratory tract. The efficacy of probiotics in several respiratory infections has been previously studied. Therefore, this study aimed to understand the available safety information provided by different species of probiotic bacteria in the process of improving the symptoms of respiratory infection caused by the COVID-19 virus.
... To inhibit the virus from entering human cells, blocking binding interactions (BIs) between ACE2-PD and RBD using peptide inhibitors, neutralizing antibodies and small-molecule drugs have been extensively investigated [10][11][12][13][14][15][16]. Due to their high structural compatibility with the surface of a protein target, and their abilities to disrupt protein-protein interaction, peptides can be utilized as inhibitors that disrupt ACE2-PD and RBD binding [17,18]. ...
Brought about by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease (COVID-19) pandemic has resulted in large numbers of worldwide deaths and cases. Several SARS-CoV-2 variants have evolved, and Omicron (B.1.1.529) was one of the important variants of concern. It gets inside human cells by using its S1 subunit’s receptor-binding domain (SARS-CoV-2-RBD) to bind to Angiotensin-converting enzyme 2 receptor’s peptidase domain (ACE2-PD). Using peptides to inhibit binding interactions (BIs) between ACE2-PD and SARS-CoV-2-RBD is one of promising COVID-19 therapies. Employing computational protein design (CPD) as well as molecular dynamics (MD), this study used ACE2-PD’s α1 helix to generate novel 25-mer peptide binders (SPB25) of Omicron RBD that have predicted binding affinities (ΔG bind (MM‑GBSA) ) better than ACE2 by increasing favorable BIs between SPB25 and the conserved residues of RBD. Results from MD and the MM-GBSA method identified two best designed peptides (SPB25 T7L/K11A and SPB25 T7L/K11L with ΔG bind (MM‑GBSA) of −92.4 ± 0.4 and −95.7 ± 0.5 kcal/mol, respectively) that have better ΔG bind (MM‑GBSA) to Omicron RBD than ACE2 (−87.9 ± 0.5 kcal/mol) and SPB25 (−71.6 ± 0.5 kcal/mol). Additionally, they were predicted to have slightly higher stabilities, based on their percent helicities in water, than SBP1 (the experimentally proven inhibitor of SARS-CoV-2-RBD). Our two best designed SPB25s are promising candidates as omicron variant inhibitors.
... It has been shown that the transmembrane protein ACE2 serves as a receptor for the spike (S) protein of the SARS-CoV-2 virus. [4][5][6][7] This S protein consists of two subunits as S1 and S2. When S1 binds to ACE2, S2 is cleaved by transmembrane serine protease 2 (TMPRSS2) and the virus is taken inside the cells by invagination of the cell membrane. ...
Objective: ACE2 and TMPRSS2 proteins have received increased attention gained emphasis together with the pandemic COVID-19. These proteins have roles in respiratory and hypertension disorders as well as cardiovascular and renal diseases. The objective of this work was to examine the mRNA and protein levels of ACE2 and TMPRSS2 in cell lines derived from various tissue origins. Methods: After the growth of 14 different cell lines, protein and mRNA were isolated from the cell pellets. The amounts of mRNAs and proteins were then determined and quantified using RT-PCR and ELISA. Results: Findings showed that VERO, HEK293T, and VERO E6 cell lines significantly differed from others in the mRNA levels of both the ACE2 and TMPRSS2 genes. In protein levels obtained using ELISA, PNT1A cell line had the highest level of ACE2 protein expression, while for TMPRSS2, A549 had the highest level of protein expression. Conclusion: It was showed in this study how the expressions of ACE2 and TMPRSS2 depend on the cell type. This may be an explanation for why virulence entrance differs in different types of tissues. It is thought that HEK293T cells with high levels of both genes may be a suitable option for studies at the RNA level by using these two genes. MCF7 may be a good option for studies at the protein level. Given the high levels of mRNA expression of both genes, it may be inferred that cells derived from the kidney were among those that were most susceptible to virus entry.
... It is also expressed in the epithelial cells of the kidney, heart, lung, small intestine, and liver and has roles in fluid homeostasis, cardiac contractility, and amino acid absorption, as well as the prevention of pulmonary fibrosis and hypertension. ACE2 also acts as a functional receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 to facilitate viral entry into host cells [4,10]. Inhibitors of the ACE2 and SARS-CoV-2 interaction may be beneficial against viral infection in the treatment of COVID-19. ...
Peptides from Stolephorus indicus (Anchovies) meat lysate were generated using a Bacillus subtilis cysteine protease. The peptides were generated by enzyme hydrolysis after which the hydrolysate containing peptides were analysed by LC-MS/MS. Computer aided analysis of peptides using CASTp server and GOLD software show four peptides having ACE2 inhibitory activity. Further, peptides 1 (8 amino acids), 2 (8 amino acid), 5 (9 amino acids) and 11 (12 amino acids) showed good docking features for binding to ACE2 enzyme active sites, mainly by hydrogen bonding. Peptide 1 (8 amino acids-octa-peptide) having the highest docking score was tested in vitro for ACE2 binding and showed up to 40 % inhibition of ACE2 activity at a concentration of 10mM. Hence, this octa-peptide has a potential role in applications involving ACE2 inhibition thereby leading to the prevention of binding of spike glycoprotein to ACE2 receptor.
... Down-regulation of ACE2 expression during SARS-CoV-2 infection leads to an increase in plasma angiotensin II levels, which in turn correlate with the overall viral load and the severity of lung injury (62). ...
... However, a range of therapeutic options are being investigated such as remdesivir and lopinavir, convalescent plasma therapy, phytochemicals, lianhuaqingwen, chloroquine and hydroxychloroquine, and herbal medications. [94][95][96] Recent studies showed that niclosamide provides distinct advantages over other drugs currently being investigated in the COVID-19 space because it can act as an immunomodulator as well as an anti-bacteriostatic agent. [97] In vitro studies on interferon-α, an antiviral medication routinely used to treat hepatitis, demonstrated that it inhibits SARS-CoV-2 replication. ...
Patients with COVID-19 exhibit similar symptoms to neonatal respiratory distress syndrome. SARS-CoV-2 spike protein has been shown to target alveolar type 2 lung cells which synthesize and secrete endogenous surfactants leading to acute respiratory distress syndrome in some patients. This was proven by post-mortem histopathological findings revealing desquamated alveolar type 2 cells. Surfactant use in patients with COVID-19 respiratory distress syndrome results in marked improvement in respiratory parameters but not mortality which needs further clinical trials comparing surfactant formulas and modes of administration to decrease the mortality. In addition, surfactants could be a promising vehicle for specific drug delivery as a liposomal carrier, which requires more and more challenging efforts. In this review, we highlight the current reviews and two clinical trials on exogenous surfactant therapy in COVID-19-associated respiratory distress in adults, and how surfactant could be a promising drug to help fight the COVID-19 infection.
... This finding has opened debate about whether ACE inhibitors and/or angiotensin receptor blockers could be used to treat COVID-19 or, conversely, aggravate the disease [106]. ACE inhibitors can cause a decrease in angiotensin I levels, triggering a possible negative feedback loop, which in turn activates more ACE2 receptors to interact with available angiotensin I substrates. ...
SARS-CoV-2, a novel coronavirus, is currently represented a major public health concern. The high transmission rate of this virus increases the mortality rate worldwide. To date, significant efforts and restricted regulations were performed around the world to control this crisis effectively, but unfortunately, there is no specific and successful therapy for COVID-19. Many approaches have been repurposed for SARS-CoV-2 treatment such as antivirals and anti-inflammatories. Furthermore, antibody therapies are one of the main and important approaches of SARS-CoV-2 infection treatment. In recent trials, various immunotherapeutic interventions such as convalescent plasma therapy and monoclonal antibodies, as well as immunomodulatory agents are being proposed. However, the development of a vaccine that provides durable protective immunity will be the most effective therapy for controlling possible epidemics of this virus. The current review summarized all the proposed therapeutic approaches together with information on their safety and efficacy in treating COVID-19, as well as the vaccine candidates. The provided comprehensive information regarding the applied therapeutic strategies against COVID-19 might help the scientific community in any progress toward the treatment of COVID-19 infection.
... However, the length of hospitalization and some patients' clinical symptoms may get better. This is while several papers persist in proposing focusing on Ang-II (44) or redox signals (45) as a viable therapeutic for COVID-19. The challenge is to intervene in the signaling cascades triggered by Ang-II without affecting individuals' renal function and hemodynamics. ...
Background: Whilst over two years have passed since the COVID-19 pandemic's emergence, the proper management of the disease remains challenging. N- acetylcysteine (NAC) as a potentially effective therapeutic option has been suggested by studies, while the exact clinical role of this agent is yet to be evaluated.
Methods: This prospective case-control study was conducted in a major referral respiratory center in Tehran, Iran. We enrolled 217 patients treated with an intravenous daily dose of 1500 mg NAC as a case group; and 245 control patients who did not receive NAC. Two groups were matched based on other treatments, socio- demographics, medical history, and comorbidities.
Results: After ten days of adjuvant therapy with NAC, patients in the NAC group and control group had median room-air SpO2 of 91% and 88%, respectively (P=0.02). Also, the SpO2 to FiO2 ratio had a median of 463 and 421 in the case and control groups, respectively (P=0.01). Furthermore, the case group's hospitalization period was three days shorter (P=0.002). Further, cough, dyspnea, and decreased appetite were reported to have a significantly lower incidence in the case group (P=0.03, 0.001, 0.008).
Conclusion: We showed that a daily intravenous dose of NAC in hospitalized COVID- 19 patients could shorten the hospital stay and improve some clinical symptoms; however, it does not remarkably improve the risk of ICU admission and the 28 days in- hospital mortality rate.
Keywords: N-acetylcysteine; Covid-19; Hospitalization
... This leads to the speculation that ARBs may be an effective therapeutic tool in the prevention of severe COVID-19 [147]. Several clinical studies have demonstrated an association between ARBs and improved outcomes in hypertensive COVID-19 patients [148][149][150][151][152] (Table 1). The use of ARBs has been seen to significantly decrease disease severity during hospitalization compared to non-ARB RAS inhibitors [153]. ...
Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 (COVID-19). CVDs have been identified as major risk factors for severe and fatal COVID-19 states. The renin–angiotensin system (RAS) is an important regulatory system in cardiovascular homeostasis. However, its dysregulation is observed in CVDs, where upregulation of angiotensin type 1 receptor (AT1R) signaling via angiotensin II (AngII) leads to the AngII-dependent pathogenic development of CVDs. Additionally, the interaction between the spike protein of severe acute respiratory syndrome coronavirus 2 with angiotensin-converting enzyme 2 leads to the downregulation of the latter, resulting in the dysregulation of the RAS. This dysregulation favors AngII/AT1R toxic signaling pathways, providing a mechanical link between cardiovascular pathology and COVID-19. Therefore, inhibiting AngII/AT1R signaling through angiotensin receptor blockers (ARBs) has been indicated as a promising therapeutic approach to the treatment of COVID-19. Herein, we review the role of AngII in CVDs and its upregulation in COVID-19. We also provide a future direction for the potential implication of a novel class of ARBs called bisartans, which are speculated to contain multifunctional targeting towards COVID-19.
... Therefore, the development of Spike-ACE2 protein-protein inhibitors could be used to prevent the infection process of SARS-CoV-2. [37][38][39] Consequently, molecular docking studies have been performed to investigate the potential ability of these compounds as antiviral agents against coronavirus. The findings are promising in terms of binding energies towards the active residues of ACE2 and spike protein. ...
In the present work, a new series of imidazo[1,2-a]pyrimidine Schiff base derivatives have been obtained using an easy and conventional synthetic route. The synthesized compounds were spectroscopically characterized using 1H, 13C NMR, LC-MS(ESI), and FT-IR techniques. Green metric calculations indicate adherence to several green chemistry principles. The energy of Frontier Molecular Orbitals (FMO), Molecular Electrostatic Potential (MEP), Quantum Theory of Atoms in Molecules (QTAIM), and Reduced Density Gradient (RDG) were determined by the Density Functional Theory (DFT) method at B3LYP/6-31G (d, p) as the basis set. Moreover, molecular docking studies targeting the human ACE2 and the spike, key entrance proteins of the severe acute respiratory syndrome coronavirus-2 were carried out along with hACE2 natural ligand Angiotensin II, the MLN-4760 inhibitor as well as the Cannabidiolic Acid CBDA which has been demonstrated to bind to the spike protein and block cell entry. The molecular modelling results showed auspicious results in terms of binding affinity as the top-scoring compound exhibited a remarkable affinity (-9.1 and -7.3 kcal/mol) to the ACE2 and spike protein respectively compared to CBDA (-5.7 kcal/mol), the MLN-4760 inhibitor (-7.3 kcal/mol), and angiotensin II (-9.2 kcal/mol). These findings suggest that the synthesized compounds may potentially act as effective entrance inhibitors, preventing the SARS-CoV-2 infection of human cells. Furthermore, in silico, ADMET, and drug-likeness prediction expressed promising drug-like characteristics.
... 316 The increased ACE2 level promotes more conversion of angiotensin I to angiotensin-II, which may lead to severe lung impairment. 317 Thus, the combination of angiotensin receptor blockers with ACE2 inhibitors may be a potential and effective strategy for COVID-19 treatment by reducing vasoconstriction, cardiac stress, and pro-fibrotic effects of angiotensin-II in lungs. 318 Thus, researchers and pharmaceutical industries must draw their attention to this strategy for drug discovery for COVID-19 treatment. ...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
... The disease severity and mortality of COVID- 19 have been reported to be increased in patients suffering from other chronic diseases such as cancer, diabetes, hypertension and cardiovascular problems. This was further evidenced in the patients who have been treated with anti-hypertensive drugs such as ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [9,[12][13][14][15][16][17][18]. In parallel, studies have shown that ACEIs and ARBs resulted in an upregulation of ACE2, favoring the entry and replication of the virus [18]. ...
The coronavirus disease-19 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the molecular and cellular levels, the SARS-CoV-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2). Here, we wanted to investigate if other molecular targets and pathways may be used by SARS-CoV-2. We investigated the possibility of the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation were examined upon cell treatment with the recombinant full spike 1 S protein or RBD. We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway. Our study suggests the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and COVID-19 pathology. This may open new perspectives in the treatment of COVID-19 patients by targeting EGFR.
... As mentioned above, S-proteins are composed of two functional units, S1 and S2. S1 contains the RBD, which binds directly to ACE-2, while the function of S2 is the fusion with the host cell membrane (Gurwitz, 2020;Leung et al., 2020;Machhi et al., 2020;. ...
An outbreak of coronavirus SARS-CoV-2 infection in December 2019 in Wuhan, a province of Chi¬na, has caused a worldwide pandemic that led to devastating effects on healthcare systems and the econ¬omy worldwide. The contagiousness of the infection and the consequences of the disease in everyday life highlighted the great need for a suitable treatment against coronavirus as soon as possible. Therefore, lots of scientists all around the world focused on the discovery of a proper therapy against the virus. The pres¬ent article explains the structure of the virus, the pathophysiology of the infection with SARS-CoV-2, and various therapies against SARS-CoV-2. The first data that concern the effectiveness of vaccines from the countries that have already started mass vaccinations are positive. However, it is very early to conclude about the efficacy of vaccines in the population. The appearance of novel virus mutations raises concerns and forces some countries to impose further restrictions. The latest and the most contagious variant, known as Omicron, seems to decrease the global pandemic significantly. New SARS-CoV-2 therapies are suggest¬ed based on antisense technology.
... In March 2020, there was concern raised that renin-angiotensin-system (RAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptors blockers (ARBs), increased the risk of SARS-CoV-2 infection and the severity from COVID-19. 1 This concern may have arisen from several studies showing SARS-CoV-2 bound to ACE2, which served as an entry of SARS-CoV-2 into cells. [2][3][4] Also, some animal models showed that RAS inhibition upregulates the expression of ACE2. ...
Objective:
In March and April 2020, medical societies published statements recommending continued use of renin-angiotensin-system (RAS) inhibitors despite theoretical concerns that these medications could increase COVID-19 severity. Determining if patients discontinued RAS inhibitors during the COVID-19 pandemic could inform responses to future public health emergencies.
Methods:
We analyzed claims data from US adults with health insurance in the Marketscan database. We identified patients who filled a RAS inhibitor and were persistent, defined by not having a ≥30-day gap without medication available, and high adherence, defined by having medication available on ≥80% of days, from March 2019 to February 2020. Among these patients, we estimated the proportion who discontinued their RAS inhibitor (i.e., had ≥30 consecutive days without a RAS inhibitor available to take) between March and August 2020. For comparison, we estimated the proportion of patients that discontinued a RAS inhibitor between March and August 2019 after being persistent with high adherence from March 2018 to February 2019.
Results:
Among 816,380 adults who were persistent and adherent to a RAS inhibitor from March 2019 to February 2020, 10.8% discontinued this medication between March and August 2020. Among 822,873 adults who were persistent and adherent to a RAS inhibitor from March 2018 to February 2019, 11.7% discontinued this medication between March and August 2019. The multivariable-adjusted relative risk for RAS inhibitor discontinuation in 2020 versus 2019 was 0.94 (95%CI 0.93-0.95).
Conclusion:
There was no evidence of an increase in RAS inhibitor discontinuation during the early stage of the COVID-19 pandemic.
... It is hypothesized that the administration of these blockers may increase the risk of developing a severe case of COVID-19 (James, 2020), as those blockers can increase the number of hACE2, which is the entrance of the virus into the body. Nonetheless, that may be beneficial, as the cellular machinery that the virus needs to reproduce would be busier producing hACE2 than copies of the virus (Gurwitz, 2020). Both theories require a greater understanding of the mechanism of these blockers in the human body. ...
Synthetic biology aims to develop cells with entirely new functions not found in nature. These functions are manifested through pathways created of genes from other microorganisms linked by molecular techniques such as Bio-Brick Assembly. Some of these linkages can adopt a Boolean behavior and generate what is known as a genetic circuit that is mainly composed of the functional parts of a gene (Promoter, RBS, ORF, Terminator). These interchangeable parts form what is called a Bio-Brick, which can act as a logical gateway by showing an excellent stability and the activation of genetic memory that can lasts after several generations. As a result of the different types of behavior that Bio-Bricks present, they are highly attractive for the industry because it would be enough to choose the best type of circuit for multiple applications both in the biomedical industry (cancer drugs, malaria, specific antibodies, microbiome engineering) or the energy industry in order to produce second-generation biofuels that can compete effectively with fossil fuels; it has also been discovered that due to its usefulness in different fields, it represents a solution to problems such as high greenhouse gas emissions or the current pandemic caused by the appearance of the SARS-CoV-2 virus. Biología sintética: Sobre el desarrollo de circuitos genéticos y su aplicación en biociencias y en biocombustibles resumen La biología sintética tiene como objetivo desarrollar células con funciones totalmente nuevas y que no se encuentran en su naturaleza. Estas funciones se manifiestan a través de rutas creadas a partir de genes provenientes de otros microorganismos vinculados por técnicas moleculares como el ensamblaje de Bio-Brick. Algunos de estos enlaces pueden adoptar un comportamiento booleano y generar lo que se conoce como un circuito genético, compuesto principalmente por las partes funcionales de un gen (Promotor, RBS, ORF, Terminador). Estas piezas intercambiables forman lo que se conoce como Bio-Brick, que actúa como una puerta lógica al mostrar una estabilidad excelente y una memoria genética que perdura después de varias generaciones. Por los distintos tipos de comportamiento que presentan los Bio-Bricks, son muy atractivos para la industria, ya que con solo elegir un tipo de circuito sus aplicaciones son diversas, por ejemplo en la industria biomédica para (medicamentos contra el cáncer, la malaria, anticuerpos específicos e ingeniería del microbioma), o en la industria energética para (generar biocombustibles de segunda generación que compitan eficazmente con los combustibles fósiles; también se ha descubierto que por su utilidad en diferentes ámbitos, representa una solución a problemas como las altas emisiones de gases de efecto invernadero o la actual pandemia provocada por la aparición del SARS-CoV-2. Palabras clave: biología sintética, circuitos genéticos, Bio-Bricks, ingeniería del microbioma, rutas sintéticas, producción de biocombustibles. Artículo recibido el 15 de septiembre del 2021. Artículo aceptado el 10 de marzo del 2023. ARTÍCULO DE REVISIÓN
... Besides NAbs, several compounds capable of inhibiting the RBD-ACE2 interaction have also been considered for the treatment of COVID-19 [118,119]. Indeed, ACE2 was one of the first substances suggested for the treatment of COVID-19, because ACE2 in solution potently blocks the binding of RBD to cell-bound ACE2 [120][121][122]. However, the approach of systemically administering ACE2 is hampered by several problems. ...
More than three years ago, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused the unforeseen COVID-19 pandemic with millions of deaths. In the meantime, SARS-CoV-2 has become endemic and is now part of the repertoire of viruses causing seasonal severe respiratory infections. Due to several factors, among them the development of SARS-CoV-2 immunity through natural infection, vaccination and the current dominance of seemingly less pathogenic strains belonging to the omicron lineage, the COVID-19 situation has stabilized. However, several challenges remain and the possible new occurrence of highly pathogenic variants remains a threat. Here we review the development, features and importance of assays measuring SARS-CoV-2 neutralizing antibodies (NAbs). In particular we focus on in vitro infection assays and molecular interaction assays studying the binding of the receptor binding domain (RBD) with its cognate cellular receptor ACE2. These assays, but not the measurement of SARS-CoV-2-specific antibodies per se, can inform us of whether antibodies produced by convalescent or vaccinated subjects may protect against the infection and thus have the potential to predict the risk of becoming newly infected. This information is extremely important given the fact that a considerable number of subjects, in particular vulnerable persons, respond poorly to the vaccination with the production of neutralizing antibodies. Furthermore, these assays allow to determine and evaluate the virus-neutralizing capacity of antibodies induced by vaccines and administration of plasma-, immunoglobulin preparations, monoclonal antibodies, ACE2 variants or synthetic compounds to be used for therapy of COVID-19 and assist in the preclinical evaluation of vaccines. Both types of assays can be relatively quickly adapted to newly emerging virus variants to inform us about the magnitude of cross-neutralization, which may even allow us to estimate the risk of becoming infected by newly appearing virus variants. Given the paramount importance of the infection and interaction assays we discuss their specific features, possible advantages and disadvantages, technical aspects and not yet fully resolved issues, such as cut-off levels predicting the degree of in vivo protection.
... ARB terbukti dapat mengurangi derajat inflamasi, mempunyai fungsi proteksi terhadap mitokondria, menjaga sensitivitas insulin dan metabolisme energi, serta menstabilkan adanya fungsi kaskade koagulasi. 10,27,33 Kegunaan ARB tidak sebatas agen antihipertensi yang ditolerir pasien usia tua, namun juga sebagai terapi adjuvan bagi pasien dengan berbagai komorbid lain seperti diabetes, penyakit ginjal kronik, gagal jantung kongesti, dan penyakit yang berkaitan dengan sistem serebrovaskular yang merupakan merupakan komorbid penentu luaran yang kurang baik pada pasien dengan COVID-19. 34,35 ARB bersifat protektif terhadap cedera paru berat terkait pneumonia, sepsis, influenza, dan infeksi SARS-CoV, 36 bahkan berperan terhadap fungsi kognisi, menurunkan inflamasi otak, bersifat protektif terhadap aliran darah dan fungsi sawar darah otak, menurunkan kecemasan dan stres, 37 serta bermanfaat dalam mengembalikan ekspresi dari gen-gen yang terkait dengan proses penuaan seperti signaling p53 ke fungsi normalnya. ...
Coronavirus disease 2019 (COVID-19) akibat severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) menyebabkan kerusakan paru dan mortalitas bagi penderitanya. Di awal pandemi COVID-19, penggunaan obat antihipertensi RAS blocker diduga berperan dalam keluaran yang kurang baik pada pasien COVID-19 dengan hipertensi karena secara teoritis akan meningkatkan ekspresi ACE2 dan memperbanyak jalan masuk virus ke dalam organ. Beberapa penelitian terkini menyatakan sebaliknya. Studi preliminary menunjukkan penurunan mortalitas dan luaran kritis pasien dengan terapi ARB. Candesartan dalam studi in-vitro dapat mengurangi badai sitokin pada COVID-19 dan berpotensi mengurangi efek destruktif lain dari infeksi SARS-CoV-2. Candesartan dapat menekan inflamasi berlebih dan mengurangi stres oksidatif, sehingga berpotensi bermanfaat dalam terapi infeksi akut SARS-CoV-2. Candesartan juga bermanfaat mengurangi komplikasi jangka panjang, bermanfaat untuk fungsi paru dan organ-organ lainnya. Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) infection causes lung damage and mortality. At early COVID-19 pandemic stage, use of RAS blocker as antihypertensive drugs was discouraged because it potentially increases the expression of ACE2, therefore increase viral entry into organs. Nevertheless, recent researches suggests otherwise. Preliminary studies has shown reduction in mortality and critical outcomes of patients with ARB therapy. Candesartan in-vitro wasable to reduce cytokine storm in COVID-19 and potentially reduce other destructive effects of SARS-CoV-2 infection by surpressing excessive inflammation and reducing oxidative stress; potentially benefits acute treatment of SARS-CoV-2 infection. Candesartan also play a role in reducing long-term complications of the disease, improving lung function as well as other organs.
... An efficient therapeutic to mitigate the COVID-19 has been carried out at early stages of the outbreak. Thus, angiotensin receptor 1 (AT1R) blockers (Losartan) has been reported to mitigate the disease [36]. Others have cloned and expressed 26 SARS-CoV-2 proteins in human cell line. ...
SARS-CoV-2 is a highly pathogenic novel ongoing-pandemic virus. It causes COVID-19. Little is known about SARS-CoV-2 biology, countermeasure, and its origin. SARS-CoV-2 is characterized by high infectiousness and sever pathogenesis. COVID-19 crosses the bounders of all continents in a high spreading manner. Here, several aspects regarding the origin and the molecular structure of this novel virus as well as the production of effective vaccines have been addressed. This article illustrated that SARS-CoV-2 was not being recombined inside laboratory and it has a complicated genome that led to sophisticated pathogenesis. Additionally, an important structural protein known as spike S was demonstrated by researchers as an important protein used by the virus for host cell entry as well as for vaccine development. However, the efforts for viral diagnosis and genomic demonstration as well as vaccine production are promising to tackle COVID-19. These perspectives will help in COVID-19 control. However, further investigations are urgently needed to figure out which controlling tactic is more efficient not only in the case of SARS-CoV-2 but also for future pandemics.
... Down-regulation of ACE2 expression during SARS-CoV-2 infection leads to an increase in plasma angiotensin II levels, which in turn correlate with the overall viral load and the severity of lung injury (62). ...
... Recent research has shown that the use of ACEIs and ARBs may increase the expression of the ACE2 receptor in mice, and these results have raised concerns that patients using these medications are more susceptible to COVID-19 and may be more affected than people who do not use these medications [21][22][23]. On the other hand, it has also been hypothesized that increasing the number of ACE2 receptors can improve outcomes in patients with acute lung injury caused by adult respiratory distress syndrome with SARS-CoV-2 infection [24]. Also, some evidence shows that stopping these drugs worsens the condition of patients infected with SARS-CoV-2, and physicians believe these drugs should be continued [25]. ...
Background and Aim: COVID-19 is an acute respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A few studies with conflicting results have been performed to evaluate the relationship between the use of angiotensin system inhibitors and COVID-19 outcomes. Therefore, this study was performed to compare the clinical and paraclinical characteristics of patients with COVID-19 in two groups of patients treated with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and the control group (no history of ACEIs/ARBs) in Kamkar and Shahid Beheshti hospitals in Qom City, Iran from March 14, 2019, to the end of September 21, 2020. Materials and Methods: This retrospective descriptive study was performed by reviewing the medical record of 359 patients with COVID-19, which was confirmed by a physician via lung scan or reverse transcription polymerase chain reaction (RT-PCR). We used the independent t test to compare quantitative variables and the Chi-square test to analyze qualitative variables. Results: The common clinical symptoms, number of hospitalization days, oxygen saturation, and lung involvement were not significantly different between the two groups. Weakness, nausea, and sweating were significantly reduced in the control group compared to the ACEIs/ARBs group (P<0.05). Regarding the biochemical study, the patients’ hemoglobin levels and lymphocyte count on the first day of hospitalization in the ACEIs/ARBs group were significantly lower than the control (P<0.05) Conclusion: These findings do not provide evidence of adverse or beneficial effects of angiotensin system inhibitors, so we require more detailed studies with a larger sample size.
... Since the end of 2019, when SARS-CoV-2 appeared for the first time in Wuhan [35,36,37], a lot of research has been devoted to understanding and characterizing the molecular basis of the infection. ACE2 was soon suggested to be the mediator of the viral invasion of the host cells through its binding with the spike protein of SARS-CoV-2, with the concomitant downregulation of ACE2-involving pathways [38,39]. These findings were largely inspired by the similarity with previous SARS-CoV infections [32,33,34]. ...
The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, so many studies have been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical and experimental analyzes, which, for example, quantify the levels and activity of RAS components, in order to disentangle the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. Finally, we discussed the effects of some RAS-targeting drugs, and how they could potentially contribute to restore the normal RAS functionality and minimize COVID-19 severity.
... Results of animal studies have found that ACEIs potentially reduce Ang-II and increase Ang-(1-7) levels in the plasma and ARBs potentially increase Ang-II, Ang-(1-7) levels, as well as the activity of ACE2. Therefore, ACEIs/ARBs potentially attenuate lung injury by hindering the classical RAAS axis (ACE-Ang II-AT1R) and aggrandizing the new ACE2-Ang II-Ang-(1-7)/Mas receptor pathway [10,49]. ...
Abstract Background The effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on mortality was preliminarily explored through the comparison of ACEIs/ARBs with non-ACEIs/ARBs in patients with coronavirus disease 2019 (COVID-19). Reaching a conclusion on whether previous ACEI/ARB treatment should be continued in view of the different ACE2 levels in the comparison groups was not unimpeachable. Therefore, this study aimed to further elucidate the effect of ACEI/ARB continuation on hospital mortality, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) in the same patient population. Methods We searched PubMed, the Cochrane Library, Ovid, and Embase for relevant articles published between December 1, 2019 and April 30, 2022. Continuation of ACEI/ARB use after hospitalization due to COVID-19 was considered as an exposure and discontinuation of ACEI/ARB considered as a control. The primary outcome was hospital mortality, and the secondary outcomes included 30-day mortality, rate of ICU admission, IMV, and other clinical outcomes. Results Seven observational studies and four randomized controlled trials involving 2823 patients were included. The pooled hospital mortality in the continuation group (13.04%, 158/1212) was significantly lower than that (22.15%, 278/1255) in the discontinuation group (risk ratio [RR] = 0.45; 95% confidence interval [CI], 0.28–0.72; P = 0.001). Continuation of ACEI/ARB use was associated with lower rates of ICU admission (10.5% versus 16.2%, RR = 0.63; 95% CI 0.5–0.79; P
... 26 Other sources have also suggested that ACE2 may protect patients from organ injury and improve clinical outcomes in infected patients. 27,28 In addition to the higher mortality in male patients, our study found that there was no statistically significant difference in the length of hospital stay according to the gender of the patient (P > 0.05). Male individuals may carry a higher risk for morbidity and mortality compared with females, but it can be said that the gender factor does not affect the process from illness to death. ...
Aim
To examine the age, gender and chronic disease status of patients who died due to Covid-19 during the pandemic process and the effects of these diseases on their deaths.
Material and Method
It was a retrospective retrospective analysis with 2715 patients. The statistics of the patients who met the research criteria were evaluated from the hospital database. Patients were evaluated in terms of age, gender, length of hospital stay, presence of chronic disease, and Modified Comorbidity Index Scores.
Results
It was determined that the Modified Charlson Comorbidity Index (MCCI) score mean of the patients was 4.74±2.07 and MCCI scores of 56.9% were serious. There was a statistically significant difference in the length of hospital stay according to the number of diseases the patient had, age, and MCCI score. It was determined that there was a statistically significant, negative and high-level correlation between MCCI score and the length of hospital stay (r=-0.075: p=0.001).
Conclusion and recommendations
Age, comorbidity score, and the number of comorbidities were found to affect the length of hospital stay, ie death. For this reason, it is recommended to use comorbidity indices in health protection and development studies, in the field, as well as in the clinics.
... Previous studies have reported that ARBs could diminish the potential for acute respiratory distress syndrome, myocarditis, or acute kidney injury, occurring in COVID-19 patients. ARBs have been suggested to treat COVID-19 and its complications (Gurwitz, 2020;Rothlin et al., 2020;Saavedra, 2020). ...
Purpose of the study: As demonstrated by numerous epidemiological studies, the high incidence of hypertension among patients with coronavirus disease 2019 (COVID-2019) appears to be associated with an elevated risk of mortality. The angiotensin-converting enzyme (ACE) system is not expressed uniformly throughout the human population, and contemporary variations may account for part of the global disparities in infection prevalence. In addition, animal investigations have demonstrated that the ACE2 receptor is a potential infection route for the COVID-19-causing SARS-CoV-2 virus. As two-thirds of hypertension patients take ACE inhibitors/angiotensin receptor blockers, a number of concerns have been raised regarding the harmful or beneficial effects of contemporary antihypertensive medications in COVID-19. This study presents the most recent evidence for and against the impact of ACE blockade administration in the age of COVID-19 on the cohort of hypertension patients in Bangladesh (N = 300). Methods: We included in this study 300 patients who had a record of a COVID-19 test performed between July 2021 and September 2021 using RT-PCR. All the patients had a history of hypertension two years before the index date, based on the International Classification of Diseases codes (Tenth Revision, Clinical Modification, ICD-10-CM). All of them have been taking anti-hypertensive drugs for 1–2 years. We used logistic regression to estimate the odds ratio (OR) and the 95% confidence interval (CI) of COVID-19 severity in patients prescribed Angiotensin Receptor Blockers (ARB) versus those not prescribed ARB. We selected a cohort of 300 Bangladeshi patients who were covid posi tive and had been taking hypertensive medications for 1-5 years. Results: Among COVID-19-positive patients with hypertension, the use of ARB is associated with increased odds of hospitalization, including all patients admitted to ICU or CCU (OR = 1.008, (0.440, 2.309) and OR= 2.31, (0.024, 2.452) respectively). Participants receiving ARB have a lower odds ratio of using BiPAP, CPAP, and Ventilation (0.592, 0.010, and 0.031, respectively; p-value < 0.5) compared to the non-ARB users. Research Implications: We noticed a statistically significant association between ARB administration and mechanical ventilation in our study. Since ARB use was also related to a decreased likelihood of needing additional oxygen support, such as nasal cannula, BiPAP, and CPAP, there is sufficient evidence from other clinical factors to indicate a consistent connection between ARB use and oxygen assistance among covid-positive patients. Further research is required to determine the molecular relationship between ARB use and oxygen level in Covid-positive individuals. Bioresearch Commu. 9(1): 1180-1195, 2023 (January)
... [24] Furthermore, it was discussed that individuals with CKD have elevated levels of circulating angiotensin-converting enzyme 2 (ACE2), [25] which accelerates the SARS-CoV-2 entrance and may subsequently be downregulated by the virus, leading to unregulated angiotensin-2 activity and multiple organ failure. [26][27][28] Furthermore, it should be mentioned that most of the included patients in this meta-analysis had serum creatinine within the normal range which leads to the hypothesis of whether different stages of CKD are correlated with COVID-19. The present study was designed to answer this issue but failed to provide any significant association. ...
Background: To organize efforts to manage the coronavirus disease 2019 (COVID-19), it is necessary to understand which groups are at higher risk of infection. Kidney disease seems to be substantial in COVID-19 patients, but there are limited data on COVID-19 incidence and fatality among chronic kidney disease (CKD) patients. In this study, we intend to examine the association between CKD and susceptibility to COVID-19 infection.
Materials and Methods: Participants were selected from those recruited in a population-based cross-sectional survey of CKD prevalence and associated risk factors in Iranian people 18 years and older. A three-part questionnaire was used for COVID-19 infection clinical symptoms and epidemiologic and hospitalization data.
Results: A total of 962 individuals including 403 CKD patients and 559 healthy controls were recruited in this study. Healthy controls were suffering more from common cold signs, cough, fever, sore throat, headache, anosmia, dyspnea, and abdominal pain (all P < 0.05). Furthermore, the number of healthy individuals with myalgia was marginally higher compared to the CKD patients (P = 0.057). Data regarding the number of CKD patients with/without COVID-19 infection throughout different CKD stages revealed that there was no significant difference between the two groups in terms of COVID-19 infection in different stages of CKD (P = 0.956).
Conclusion: We found that some of the clinical presentations of COVID-19 including common cold symptoms, cough, fever, sore throat, headache, anosmia, dyspnea, and abdominal pain were higher among healthy individuals compared to the CKD group. On the other hand, the susceptibility to COVID-19 infection was not significantly different in various early stages of CKD.
... (30,31) Dado que la ACE2 actúa como receptor celular del SARS-CoV-2, (5) se ha propuesto que la internalización del SARS-CoV-2 reduce los niveles de ACE2 unida a membrana, lo que pudiera potenciar el daño tisular y agravar la ERC por medio del incremento de los niveles de AngII. (32) De hecho, se ha reportado un significativo incremento de AngII en una serie de 12 pacientes chinos con COVID-19, (33) aunque el significado clínico de esta observación es confuso, dada la dificultad de medir con precisión los niveles de AngII en humanos y la influencia de las alteraciones hemodinámicas asociadas a enfermedades graves. (34) Con base en las observaciones antes discutidas, se ha propuesto que el uso de agentes farmacológicos que actúan como bloqueadores del receptor de la AngII, incrementan los niveles de ACE2. ...
Introducción:
La COVID-19 ha desatado una emergencia en salud pública de carácter internacional, pues ha infescado y provocado muertes a millones de personas, desatando así una crisis humanitaria nunca antes vista. Las muertes por COVID-19 también se han asociado a la presencia de algunas enfermedades crónicas.
Objetivo:
Evaluar la asociación entre la enfermedad renal crónica y el peor pronóstico de pacientes con COVID-19.
Métodos:
Se realizó una búsqueda en las bases de datos PubMed, Scopus, EBSCO Host, Clinical Key, Hinari y Cochrane. Se consultaron artículos publicados hasta el 30 de abril de 2020. Se incluyeron artículos observacionales con información relevante respecto al desenlace de pacientes con COVID-19 y enfermedad renal crónica.
Resultados:
Fueron incluidos 13 artículos que resumen la información de 8207 pacientes, de los que 405 (4,9 %) tenían enfermedad renal crónica. Se asoció la comorbilidad con un peor pronóstico en pacientes con COVID-19, con OR = 1,99 [IC 95 %: 1,13-3,52; Z = 2,37; p = 0,02] y heterogeneidad I² = 47 %, (² = 22,47 (p = 0,03). Al eliminar los estudios con mayor contribución a la heterogeneidad, se analizó información de 5924 pacientes y hubo una mayor asociación entre la enfermedad renal crónica y el peor pronóstico, con OR = 3,02 [IC 95 %: 1,79-5,10; Z = 4,15; p < 0,0001] y heterogeneidad I² = 0%, (² = 3,78 (p = 0,88). Lo que se interpreta como que los pacientes con enfermedad renal crónica afectados con COVID-19 tienen una probabilidad tres veces mayor de presentar un peor pronóstico que la población general.
Conclusiones:
La enfermedad renal crónica empeora el pronóstico de los pacientes afectados con COVID-19.
... edu.ng Targeting the spike protein has been reported as a probable strategy for treating the disease [9,10]. Therefore, an effective therapy against SARS-COV-2 needs to be discovered. ...
SARS-CoV-2 has endangered the health of notable population of the world and hence, it attracted the attention of many researchers. In this study, we introduce two potential antiviral compounds for the treatment COVID-19 and compare it with the current reference drug. Molecular dynamics simulation and quantum theory of atoms in molecules (QTAIM) were used to study the host-guest interaction and dynamics between the nCov protein and inhibitors. Results obtained after a triplicate run of 100 ns for each compound revealed that compound B2 showed better inhibitory potential with MM-GBSA binding energy of-40.05 kcal mol-1 , compared to the referenced drug. It is worth noting that B1 had a comparable binding potential with B2, suggesting some similarity in their inhibitory features. The QTAIM results showed that Laplacian 2 ρ(r) and ellipticity (ε) were positive, indicating a stable protein-ligand interaction. The order of stability was in agreement with the MM-GBSA energy trends. The results showed that B1 and B2 can be used as a hopeful therapeutic for the cure of Covid-19. Though, a crucial trial should be done to authenticate this conclusion.
... ACE2, a homologue of Expert, is mindful for cleaving AngII to produce Ang (1-7). To apply anti-inflammatory and anti-remodeling impacts, Ang(1-7) ties and actuates the G protein-coupled Mas receptor (6)(7)(8). Within the epithelia of the lungs and small digestive system, ACE2 is ample. Most blood vessels endothelial cells, as well as blood vessel smooth muscle cells, contained it [8][9][10][11]. ...
The angiotensin-converting enzyme docks onto the spike glycoprotein on the virion outward. The dimer of the enzyme{ACE}2 is an vital step in the mechanism of life-threatening acute respiratory failure. Human cells are infected with the syndrome coronavirus 2 (SARS-CoV-2).The systemic renin-angiotensin system stifles the expression of ACE2 (RAS) imbalance and advancement of multi-organ harm. In common, the RAS triggers vasoconstriction, hypertension, inflammation, fibrosis, and proliferation through the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and triggers the switch impacts through the ACE2/ Ang (1-7)/Mas axis. The RAS may be triggered by chronic inflammation in hypertension, diabetes, heavy weight, and cancer. The ACE 2 /Ang {1-7} / Mas axis is deactivated by means of SARS-CoV-2-induced ACE2 internalization and shedding. As a result, we believe that two RAS hits are responsible for COVID-19 progression. In summary, the The ACE / Ang II/ AT1R axis is triggered by chronic inflammation, which is the first hit. The second stems from the disruption of the ACE2/Ang (1-7)/Mas axis by COVID-19 infection. Furthermore, the two RAS hits might be the primary cause of elevated numbers of death in COVID-19 patients and comorbidities, and they might be used as a clinical target for COVID-19 therapy.
... Angiotensin-converting enzyme 2 is used as a receptor-binding domain for intracellular penetration by the SARS-CoV-2 virus [20]. The RAS is regulated by ACE-2. ...
The new Severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) triggered the pandemic of COVID-19, which is currently still ongoing. In 2021 a worldwide vaccine campaign was launched, and in parallel the lines of research are continuing to target the most effective drug therapies for the treatment of COVID-19 disease. SARS-CoV‑2 enters host cells via glycoprotein angiotensin-converting enzyme 2 (ACE-2), which plays a major role in renin–angiotensin system interactions and undergoes changes in expression during metabolic and viral diseases, including COVID-19. It seems that the severe lung damage that occurs in several cases of COVID-19 disease may be connected to a deregulated expression of ACE‑2. In this manuscript we focus on the line of research that studies the pharmacological modification of ACE‑2 expression, a promising weapon to counter the severe harms caused by COVID-19.
... Съществуващите към момента на избухване на третата коронавирусна пандемия антивирусни лекарствени продукти, насочени към подобен вид заболявания, не се оказаха ефективни, въпреки факта, че SARS-CoV-2 принадлежи към същото семейството вируси. Този факт най-вероятно е обусловен от значителната разлики в структурата на отделните членове на семейството като SARS- Gurwitz, 2020). Отличиха се обаче няколко антивирусни лекарствени продукта, насочени към фармакотерапия на заболявания, предизвикани от други вируси, показващи забележителна ефикасност и срещу този причинител. ...
The global COVID-19 pandemic caused by the viral pathogen SARS-CoV-2 has surged the biomedical community into action to discover and develop effective antiviral drugs. One potential therapeutic approach currently being evaluated in multiple clinical trials is the medicinal product—remdesivir, which has had a tortuous development path over the past eight years. In essence, it is a nucleotide analog prodrug that inhibits viral replication. It was initially evaluated in clinical trials to prevent the Ebola outbreak in 2014. Subsequent evaluation by multiple virology laboratories around the world demonstrated remdesivir's ability to inhibit coronavirus replication, including the SARS-CoV-2 virus which is the cause of the current pandemic. In the presented paper, the authors provide an overview of the discovery of remdesivir, its mechanism of action, and current studies investigating its clinical effectiveness.
... An unspecific effect of infection and vaccination on the immune system and susceptibility to other infections has also been reported, albeit with discordant data [8][9][10]. Some modeling studies have suggested a possible association between influenza immunization and COVID-19 [11][12][13][14]. ...
Background:
A possible link between influenza immunization and susceptibility to complications of the COVID-19 infection has been previously suggested due to a boost in the immunity against SARS-CoV-2.
Objective:
We hypothesized that the immunity resulting from the previous influenza vaccination would boost part of the immunity against SARS-CoV-2 and aimed to analyze if COVID-19 patients could have benefited from vaccination against influenza.
Methods:
Population-based cohort study including all patients with COVID-19 registers in the primary health care (PHC) electronic records during the first wave of the COVID-19 pandemic (1st March 2020 - 30th June 2020) in Catalonia, Spain. We compared those people ever exposed to influenza vaccine before the COVID-19 infection with those never exposed. The data source is SIDIAP (Information System for Research in Primary Care), capturing PHC information of 5.8 million people from Catalonia. The main outcomes assessed during follow-up were diagnosis of pneumonia, hospital admission and mortality.
Results:
We included 309,039 COVID-19 patients and compared them according to their influenza immunization status, being 114,181 (36.9%) vaccinated at least once and 194,858 (63.1%) never vaccinated. 21,721 (19%) of the flu-vaccinated and 11,000 (5.7%) of the non-vaccinated had at least one of the outcomes assessed. Those vaccinated against flu at any time (OR 1.14, 95% CI 1.10-1.19), recently (OR 1.13, 95% CI 1.10-1.18) or recurrently (OR 1.10, 95% CI 1.05-1.15) before COVID-19 had higher risk of presenting at least one of the outcomes than those non-vaccinated. When we excluded people living in long-term care facilities, the results were similar.
Conclusions:
We were not able to find a protective role of the immunity conferred by the influenza vaccine on the outcomes of the COVID-19 infection, as the risk of COVID-19 complications was higher in the vaccinated than in the non-vaccinated. Our results correspond to the first wave of the pandemic, where more complications and mortality due to COVID-19 occurred. Despite that, our study adds more evidence to the analysis of the possible link between the quality of the immunity and the COVID-19 outcomes, particularly in the PHC setting.
Clinicaltrial:
IDI-VAC-2020-21. Estudio Posautorización con Otros Diseños diferentes al de seguimiento prospectivo, EPA-OD. 15th September 2020.
... Съществуващите към момента на избухване на третата коронавирусна пандемия антивирусни лекарствени продукти, насочени към подобен вид заболявания, не се оказаха ефективни, въпреки факта, че SARS-CoV-2 принадлежи към същото семейството вируси. Този факт най-вероятно е обусловен от значителната разлики в структурата на отделните членове на семейството като SARS- Gurwitz, 2020). Отличиха се обаче няколко антивирусни лекарствени продукта, насочени към фармакотерапия на заболявания, предизвикани от други вируси, показващи забележителна ефикасност и срещу този причинител. ...
The global COVID-19 pandemic caused by the viral pathogen SARS-CoV-2 has surged the biomedical community into action to discover and develop effective antiviral drugs. One potential therapeutic approach currently being evaluated in multiple clinical trials is the medicinal product-remdesivir, which has had a tortuous development path over the past eight years. In essence, it is a nucleotide analog prodrug that inhibits viral replication. It was initially evaluated in clinical trials to prevent the Ebola outbreak in 2014. Subsequent evaluation by multiple virology laboratories around the world demonstrated remdesivir's ability to inhibit coronavirus replication, including the SARS-CoV-2 virus which is the cause of the current pandemic. In the presented paper, the authors provide an overview of the discovery of remdesivir, its mechanism of action, and current studies investigating its clinical effectiveness.
... [23] Recently, Alacepril and lisinopril were found to interact with hACE-2. [24] Moreover, dermaseptin-S9 was able to prevent the attachment of SARS-CoV-2 spike protein to the surface of the ACE-2 receptor. [25] Besides that, alatrofloxacin, azithromycin, cefoperazone, rifapentine, and vancomycin as antibacterial drugs have been proved to bind to ACE-2 to obstruct SARS-CoV-2 binding. ...
Background: Tabebuia impetiginosa is an important medicinal plant rich in lapachol, α-lapachone, and β-lapachone known to possess several biological activities. Objective: In this study, we investigated the drug potential of lapachol, α-lapachone, and β-lapachone using molecular docking, molecular dynamic (MD), and drug-likeness properties. Materials and Methods: The computational study was performed using SwissADME software for the determination of the pharmacokinetic properties of the tested compounds. AutoDock Vina and Genetic Optimization for Ligand Docking (GOLD) were used for the docking analysis, and MD simulations were run using Schrodinger's Desmond Simulation. Results: The three compounds lapachol, α-lapachone, and β-lapachone binds to cysteine (Cys)-histidine (His) catalytic dyad (Cys145 and His41) along with the other residues with, respectively, the following docking score 48.69, 47.06, and 47.79. Against viral entry receptor, human angiotensin-converting enzyme 2 (hACE-2), α-lapachone exhibited the highest GOLD Fitness score complex (54.82) followed by lapachol (42.53) and β-lapachone and hACE-2 (38.74) generating several active sites in the target proteins. A 100 ns MDs simulation study revealed the stable conformation of bioactive compounds within the cavity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of hACE-2 protein and main protease (Mpro). From the dynamic study, it was observed that lapachol was tightly bound with catalytic dyad residue Cys145 of Mpro with more than 40% time of simulation, also post-simulation MM-GBSA binding free energy (ΔG Bind) revealed the highest energy score (−51.18 ± 5.14 kcal/mol) among the evaluated complex. Moreover, the absorption, distribution, metabolism, and excretion (ADME) properties demonstrated that the investigated compounds passed the pharmacokinetic and drug-likeness criteria without undesirable effects. Conclusion: The computational study highlighted that these compounds could be highly recommended and developed as part of an effective drug against the SARS-CoV-2 virus.
... The latter is regarded a major system protective pathway, which reduces inflammation organ fibrosis and downregulates several signaling pathways (65). ARBs also seem to be an optimal therapeutic strategy for patients with severe critical disorders (such as inflammatory lung disease, pneumonia, influenza, sepsis and Ebola), by maintaining insulin sensitivity, energy and lipid metabolism, protecting mitochondrial function and regulating the coagulation cascade (66)(67)(68). Despite the numerous clinical benefits conferred by ARBs to non-COVID patients, it is still not clear whether a similar effect would be achieved in COVID-19 patients, or whether higher ACE2 expression is responsible for a more severe disease. ...
COVID‑19 patients with severe infection have been observed to have elevated auto‑antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein‑coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL‑6, IL‑8 and TNF‑α) by immune cells. Despite the presence of AAs in severe COVID‑19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin‑angiotensin‑aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID‑19.
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19), which is associated with cardiovascular problems and serious lung damage. COVID-19 patients with comorbid conditions are at a significantly elevated risk of increased morbidity and mortality. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) are the two key host contributing factors for the severity and pathogenesis of COVID-19. The principal SARS-CoV-2 entrance receptor, ACE2, is expressed equally in most organs and produces cardio-protective vasodilators by physically degrading angiotensin II, the main controller of the Renin-Angiotensin Aldosterone System. However, treatment for cardiovascular disease (CVD) commonly involves RAAS inhibitors, which may increase ACE2 expression. Objective: To summarize the pharmacological molecular discoveries into the processes of viral infection and its consequences for cardiovascular disease and to offer suggestions for the practical management and treatment of COVID-19-related cardiovascular injury. Methods: This review focuses on the important considerations related to the cardiovascular manifestations of COVID-19 and discusses the various mechanisms of COVID-19 that contribute to its molecular and pharmacological presentation of cardiovascular injury. Results: The host-pathogen relationship began with ACE2’s attachment to the S-protein and proceeded with TMPRSS2’s proteolytic cleavage of the viral spike (S)-protein and ACE2. Currently discovered protein-protein interactions explain the uniqueness of SARS-CoV-2 infection. Conclusion: COVID-19 is associated with cardiovascular problems and serious lung damage. ACE2 and TMPRSS2 are key host contributing factors for the severity and pathogenesis of COVID-19. The molecular discoveries into the processes of viral infection and its consequences for cardiovascular disease provide important considerations for the management and treatment of COVID-19-related cardiovascular injury.
Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus to cause a global pandemic of significant human illnesses in the past two decades, following MERS and SARS (SARS). On January 30, 2020, WHO declared COVID-19 a global public health emergency. Governments enforced physical distance, hand hygiene, and personal safety equipment considering the virus’s ferocity and transmissibility. Vaccination and WHO-approved emergency antiviral medications were used to prevent and manage the COVID-19 pandemic. Some of the SARS-CoV-2 variants developed in a later phase were classified as variants of concern (VOC) by WHO because of their high virulence, increased mortality and morbidity, rendering repurposed treatments and vaccines ineffectual. Traditional herbal medications were explored widely in treating SARS-CoV-2 in India, China, Africa, and other nations. The epidemic expanded the global use of secondary metabolites-based herbal treatments. By strengthening human immunity, medicinal herbs indirectly affect the virus. Several in silico, in vitro, in vivo, and clinical investigations showed the potential of herbal medication to treat and prevent COVID-19. Earlier under similar situations, herbal medicines or plant secondary metabolites (PSM) with therapeutic potential have been used to treat several chronic diseases due to their structural diversity and abundance. Several investigations evidenced that target-based phyto-molecule or herbal formulations are appropriate alternative treatments for reducing virus entrance and replication and enhancing host immunity. In this chapter, a methodical review of reported traditional herbal medicines for COVID-19 revealed a wide variety of medicinal formulations and prospective plants that may help manage and treat SARS-CoV-2. This chapter examines herbal formulations’ active principles and mechanisms for suppressing SARS-CoV-2 infection at various levels.KeywordsSpike proteinAngiotensin-converting enzyme-2Herbal formulationsImmunityAYUSHComputational study
Drug repurposing is a cost-effective method of discovering new treatments for diseases than traditional drug development methods. It involves virtual screening of chemical candidates with the aid of computational methods like molecular docking. Drug Repurposing against SARS-CoV2 focuses on current trends in drug repurposing against the novel coronavirus strains. The book aims to give readers an overview of drug repurposing against COVID-19 and various techniques involved in the process. The book consolidates available information on the pathophysiology, drug targets, and drug repurposing against COVID-19 into a single, convenient resource. Key features -An up-to-date compilation of the evidence that supports the drug repurposing for COVID-19. -How to use repurposing of available drugs for disease therapy. -Provides an improved understanding of pathophysiology and SARS-CoV2 viral entry pathways. - Provides references for further reading
During the pandemic caused by SARS-CoV-2, cardiovascular disease has been found to be an important risk factor for COVID-19. At the same time, it turned out that patients who did not suffer from cardiovascular pathology before infection with SARS-CoV-2 often had cardiovascular complications in the form of myocarditis, arrhythmias, and heart failure. It is extremely important to elucidate the pathogenetic mechanisms that determine the relationship between COVID-19 and cardiovascular pathology. Analysis of the data of the scientific literature suggests that an imbalance in the renin-angiotensin-aldosterone system (RAAS), expressed in the hyperproduction of angiotensin II and the deficiency of angiotensin 1-7, is an important factor in the pathogenetic link that causes comorbidity of COVID-19 and cardiovascular pathology. According to modern concepts, the RAAS is a complex, multicomponent, multi-level, two-axis system that has, both cardio- and vasoprotective (ACE2/Ang1-7/MasR axis) and damaging effects on the heart and blood vessels (ACE/Ang II/AT1R axis). Patients with cardiovascular diseases, as a rule, already have an imbalance of the RAAS, characterized by hyperproduction of cardiotoxic angiotensin II. Coronavirus, interacting with ACE2 an important component of the cardioprotective axis of RAAS, and reducing its quantity and activity, increases this imbalance, which aggravates the damage to the cardiovascular system. In addition, an imbalance of RAAS can lead to an imbalance in the kallikrein-kinin system with the accumulation of vascular permeability-increasing des-Arg9-bradykinin, potentiate inflammation, create prerequisites for the development of COVID-19 associated coagulopathy and acute respiratory distress syndrome. In the pathogenetic therapy of coronavirus infection, complicated by lesions of the cardiovascular system, it may be advisable to use drugs that correct changes in the renin-angiotensin-aldosterone system.
At the beginning of the COVID-19 pandemic, there was increasing concern that therapy with renin-angiotensin-system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, might increase the risk of infection, severe illness, or death from COVID-19. The renin-angiotensin system (RAS) plays a significant role in the fibrogenesis and inflammatory destruction of numerous organs, including the liver and lungs, in COVID-19 patients. However, the clinical fate of these individuals is unknown. ACE2 catalyzes the conversion of angiotensin II to angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS axis counteracts the detrimental effects of the renin-angiotensin system (RAS), which plays a key role in maintaining physiological function. As well as the pathophysiological equilibrium of the organism. In addition to the direct viral impacts and inflammatory and immunological factors involved in the pathogenesis of COVID-19, ACE2 down regulation and an imbalance between RAS and ACE2/angiotensin-(1–7)/MAS the following infection may also contribute to multiple organ damage in COVID-19. Is. -19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a possible target for creating particular medicines, antibodies, and vaccines. Restoring the equilibrium between the RAS and ACE2/angiotensin-(1–7)/MAS may aid in the prevention of limb injuries. In this chapter, we’ll look at the role of ACE2 in COVID-19 and possible therapeutic targets for it to learn more about how to treat the pandemic.KeywordsSARS-CoV-2COVID-19Angiotensin-Converting enzyme 2Multi-organ injury
COVID-19 has become a significant public health concern that has catastrophic consequences for society. Some preliminary evidence suggests that the male reproductive system may be an infection target for SARS-CoV-2. SARS-CoV-2 may be transmitted sexually, according to preliminary research. Testicular cells exhibit a high level of the angiotensin-converting enzyme 2 (ACE2) receptor, which enhances the entry of the SARS-CoV-2 into host cells. Some instances of COVID-19 have been documented to exhibit hypogonadism during the acute stage. Furthermore, systemic inflammatory reactions triggered by SARS-CoV-2 infection may cause oxidative stress (OS), which has been shown to have profoundly deleterious consequences on testicular functioning. This work gives a clear picture of how COVID-19 may affect male reproductive systems and calls attention to the many unanswered questions about the mechanisms by which this virus can be linked to men’s health and fertility.
s
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a major public health threat to all countries worldwide. SARS-CoV-2 interactions with its receptor are the first step in the invasion of the host cell. The coronavirus spike protein (S) is crucial in binding to receptors on host cells. Additionally, targeting the SARS-CoV-2 viral receptors is considered a therapeutic option in this regard. In this review of literature, we summarized five potential host cell receptors, as host-cell surface bindings, including angiotensin-converting enzyme 2 (ACE2), neuropilin 1 (NRP-1), dipeptidyl peptidase 4 (DPP4), glucose regulated protein-78 (GRP78), and cluster of differentiation 147 (CD147) related to the SARS-CoV-2 infection. Among these targets, ACE2 was recognized as the main SARS-CoV-2 receptor, expressed at a low/moderate level in the human respiratory system, which is also involved in SARS-CoV-2 entrance, so the virus may utilize other secondary receptors. Besides ACE2, CD147 was discovered as a novel SARS-CoV-2 receptor, CD147 appears to be an alternate receptor for SARS-CoV-2 infection. NRP-1, as a single- transmembrane glycoprotein, has been recently found to operate as an entrance factor and enhance SARS Coronavirus 2 (SARS-CoV-2) infection under in-vitro. DPP4, which was discovered as the first gene clustered with ACE2, may serve as a potential SARS-CoV-2 spike protein binding target. GRP78 could be recognized as a secondary receptor for SARS-CoV-2 because it is widely expressed at substantially greater levels, rather than ACE2, in bronchial epithelial cells and the respiratory mucosa. This review highlights recent literature on this topic.
On December 1, 2021, a meeting of the Council of experts on the treatment of hypertension, coronary heart disease, and chronic heart failure during the COVID-19 pandemic was held remotely to adjust and adapt current approaches to outpatient treatment of the above pathologies under the current epidemiological situation. The meeting was attended by leading Russian specialists from federal medical research centers of cardiology and therapy.
В статье анализируются особенности этиологии и направлений возможного фармакологического воздействия на проникновение в клетки-мишени и репликацию нового коронавируса SARS-CoV-2. Несмотря на то, что во многих странах активно ведутся как клинические, так и биомедицинские исследования препаратов, которые могут быть потенциально эффективными при инфекции, вызванной новым коронавирусом, эффективный протокол ведения таких больных ни на национальном, ни на международном уровне пока не разработан. Цель статьи - представить потенциально перспективные направления этиотропной терапии коронавирусной инфекции covid-19 с учетом имеющихся на май 2020 года данных.
We analyze characteristics of etiology and possible pharmacological intervention in the penetration into target cells and replication of the new SARS-CoV-2 coronavirus. Despite both clinical and biomedical studies of medication that can be potentially effective for treating infections caused by the new coronavirus carried out internationally, an effective protocol has not been developed yet neither at the national nor international level. The research aims at presenting promising directions of etiotropic therapy of covid-19 coronavirus infection, taking into account the data available in May 2020.
COVID-19 patients with diabetes have greater mortality than those without comorbidities, but the underlying mechanisms remain unknown. This study aims to identify the mechanistic interactions between diabetes and severe COVID-19. Microparticles (MPs), the cell membrane-derived vesicles released upon cell activation, are largely increased in diabetic patients. To date, many mechanisms have been postulated for increased severity of COVID-19 in patients with underlying conditions, but the contributions of excessive MPs in diabetic patients have been overlooked. This study characterizes plasma MPs from normal and type 2 diabetic human subjects in terms of amount, cell origins, surface adhesive properties, ACE2 expression, spike protein binding capacity, and their roles in SARS-CoV-2 infection. Results showed that over 90% of plasma MPs express ACE2 that binds the spike protein of SARS-CoV-2. MPs in diabetic patients increase 13-fold in quantity and 11-fold adhesiveness when compared with normal subjects. Perfusion of human plasma with pseudotyped SARS-CoV-2 virus or spike protein-bound MPs into human endothelial cells-formed microvessels-on-a chip demonstrated that MPs from diabetic patients, not normal subjects, interact with endothelium and carry SARS-CoV-2 into cells through endocytosis, providing additional virus entry pathways and enhanced infection. Results also showed a large percentage of platelet-derived tissue factor-bearing MPs in diabetic plasma, which could contribute to thrombotic complications with SARS-CoV-2 infection. This study reveals a dual role of diabetic MPs in promoting SARS-CoV-2 entry and propagating vascular inflammation. These findings provide novel mechanistic insight into the high prevalence of COVID-19 in diabetic patients and their propensity to develop severe vascular complications.
There is a current worldwide outbreak of a new type of coronavirus (2019-nCoV), which originated from Wuhan in China and has now spread to 17 other countries. Governments are under increased pressure to stop the outbreak spiraling into a global health emergency. At this stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning outbreak control activities. This information should include reports from outbreak sites and from laboratories supporting the investigation. This paper aggregates and consolidates the virology, epidemiology, clinical management strategies from both English and Chinese literature, official news channels, and other official government documents. In addition, by fitting the number of infections with a single-term exponential model, we report that the infection is spreading at an exponential rate, with a doubling period of 1.8 days.
2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.
Objective
Since December 2019, an outbreak of corona virus disease 2019 (COVID-19) occurred in Wuhan, and rapidly spread to almost all parts of China. This was followed by prevention programs recommending Chinese medicine (CM) for the prevention. In order to provide evidence for CM recommendations, we reviewed ancient classics and human studies.
Methods
Historical records on prevention and treatment of infections in CM classics, clinical evidence of CM on the prevention of severe acute respiratory syndrome (SARS) and H1N1 influenza, and CM prevention programs issued by health authorities in China since the COVID-19 outbreak were retrieved from different databases and websites till 12 February, 2020. Research evidence included data from clinical trials, cohort or other population studies using CM for preventing contagious respiratory virus diseases.
Results
The use of CM to prevent epidemics of infectious diseases was traced back to ancient Chinese practice cited in Huangdi’s Internal Classic (Huang Di Nei Jing) where preventive effects were recorded. There were 3 studies using CM for prevention of SARS and 4 studies for H1N1 influenza. None of the participants who took CM contracted SARS in the 3 studies. The infection rate of H1N1 influenza in the CM group was significantly lower than the non-CM group (relative risk 0.36, 95% confidence interval 0.24–0.52; n=4). For prevention of COVID-19, 23 provinces in China issued CM programs. The main principles of CM use were to tonify qi to protect from external pathogens, disperse wind and discharge heat, and resolve dampness. The most frequently used herbs included Radix astragali (Huangqi), Radix glycyrrhizae (Gancao), Radix saposhnikoviae (Fangfeng), Rhizoma Atractylodis Macrocephalae (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Fructus forsythia (Lianqiao).
Conclusions
Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous population studies are warranted to confirm the potential preventive effect of CM.
Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials. Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials.
On December 31, 2019, Chinese health officials reported a cluster of cases of acute respiratory illness in persons associated with the Hunan seafood and animal market in the city of Wuhan, Hubei Province, in central China. On January 7, 2020, Chinese health officials confirmed that a novel coronavirus (2019-nCoV) was associated with this initial cluster (1). As of February 4, 2020, a total of 20,471 confirmed cases, including 2,788 (13.6%) with severe illness,* and 425 deaths (2.1%) had been reported by the National Health Commission of China (2). Cases have also been reported in 26 locations outside of mainland China, including documentation of some person-to-person transmission and one death (2). As of February 4, 11 cases had been reported in the United States. On January 30, the World Health Organization (WHO) Director-General declared that the 2019-nCoV outbreak constitutes a Public Health Emergency of International Concern.† On January 31, the U.S. Department of Health and Human Services (HHS) Secretary declared a U.S. public health emergency to respond to 2019-nCoV.§ Also on January 31, the president of the United States signed a "Proclamation on Suspension of Entry as Immigrants and Nonimmigrants of Persons who Pose a Risk of Transmitting 2019 Novel Coronavirus," which limits entry into the United States of persons who traveled to mainland China to U.S. citizens and lawful permanent residents and their families (3). CDC, multiple other federal agencies, state and local health departments, and other partners are implementing aggressive measures to slow transmission of 2019-nCoV in the United States (4,5). These measures require the identification of cases and their contacts in the United States and the appropriate assessment and care of travelers arriving from mainland China to the United States. These measures are being implemented in anticipation of additional 2019-nCoV cases in the United States. Although these measures might not prevent the eventual establishment of ongoing, widespread transmission of the virus in the United States, they are being implemented to 1) slow the spread of illness; 2) provide time to better prepare health care systems and the general public to be ready if widespread transmission with substantial associated illness occurs; and 3) better characterize 2019-nCoV infection to guide public health recommendations and the development of medical countermeasures including diagnostics, therapeutics, and vaccines. Public health authorities are monitoring the situation closely. As more is learned about this novel virus and this outbreak, CDC will rapidly incorporate new knowledge into guidance for action by CDC and state and local health departments.
The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
Background
Chronic kidney disease (CKD) is defined by abnormalities in kidney structure and/or function present for more than 3 months. Worldwide, both the incidence and prevalence rates of CKD are increasing. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance through the kidney. RAAS activation is associated with hypertension, which is directly implicated in causation and progression of CKD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be renoprotective.
Objectives
To assess genomic variants present within RAAS genes, ACE , ACE2 , AGT , AGTR1 , AGTR2 and REN , for association with CKD.
Design and data sources
A systematic review and meta-analysis of observational research was performed to evaluate the RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases with publication date between the inception of each database and 31 December 2018. Eligible articles included case–control studies of a defined kidney disease and included genotype counts.
Eligibility criteria
Any paper was removed from the analysis if it was not written in English or Spanish, was a non-human study, was a paediatric study, was not a case–control study, did not have a renal disease phenotype, did not include data for the genes, was a gene expression-based study or had a pharmaceutical drug focus.
Results
A total of 3531 studies were identified, 114 of which met the inclusion criteria. Genetic variants reported in at least three independent publications for populations with the same ethnicity were determined and quantitative analyses performed. Three variants returned significant results in populations with different ethnicities at p<0.05: ACE insertion, AGT rs699-T allele and AGTR1 rs5186-A allele; each variant was associated with a reduced risk of CKD development.
Conclusions
Further biological pathway and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.
Introduction. Studies in the 1970s and 1980s signaled concern that repeated influenza vaccination could affect vaccine protection. The antigenic distance hypothesis provided a theoretical framework to explain variability in repeat vaccination effects based on antigenic similarity between successive vaccine components and the epidemic strain.
Areas covered. A meta-analysis of vaccine effectiveness studies from 2010-11 through 2014-15 shows substantial heterogeneity in repeat vaccination effects within and between seasons and subtypes. When negative effects were observed, they were most pronounced for H3N2, especially in 2014-15 when vaccine components were unchanged and antigenically distinct from the epidemic strain. Studies of repeated vaccination across multiple seasons suggest that vaccine effectiveness may be influenced by more than one prior season. In immunogenicity studies, repeated vaccination blunts the hemagglutinin antibody response, particularly for H3N2.
Expert commentary. Substantial heterogeneity in repeated vaccination effects is not surprising given the variation in study populations and seasons, and the variable effects of antigenic distance and immunological landscape in different age groups and populations. Caution is required in the interpretation of pooled results across multiple seasons, since this can mask important variation in repeat vaccination effects between seasons. Multi-season clinical studies are needed to understand repeat vaccination effects and guide recommendations.
Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Background:
Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear.
Methods:
Of participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication (n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channel blockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, and urinary ACE2 level was measured.
Results:
Glucose and hemoglobin A1c were significantly higher in patients treated with enalapril, telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) was significantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary ACE2 level was positively correlated with systolic blood pressure (r = 0.211; P = 0.003), UACR (r = 0.367; P < 0.001), and estimated salt intake (r = 0.260; P < 0.001). Multivariable regression analysis after adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independent predictor of urinary ACE2 level.
Conclusions:
In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.
The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.
Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease.
Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated i.m. on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology.
All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS-CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence.
These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.
Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.
Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.
During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
Severe acute respiratory syndrome (SARS) is a virulent viral infection that affects a number of organs and systems. This study examined if SARS may result in cardiovascular complications.
121 patients (37.5 (SD13.2) years, 36% male) diagnosed to have SARS were assessed continuously for blood pressure, pulse, and temperature during their stay in hospital. Hypotension occurred in 61 (50.4%) patients in hospital, and was found in 28.1%, 21.5%, and 14.8% of patients during the first, second, and third week, respectively. Only one patient who had transient echocardiographic evidence of impaired left ventricular systolic function required temporary inotropic support. Tachycardia was present in 87 (71.9%) patients, and was found in 62.8%, 45.4%, and 35.5% of patients from the first to third week. It occurred independent of hypotension, and could not be explained by the presence of fever. Tachycardia was also present in 38.8% of patients at follow up. Bradycardia only occurred in 18 (14.9%) patients as a transient event. Reversible cardiomegaly was reported in 13 (10.7%) patients, but without clinical evidence of heart failure. Transient atrial fibrillation was present in one patient. Corticosteroid therapy was weakly associated with tachycardia during the second (chi(2) = 3.99, p = 0.046) and third week (chi(2) = 6.53, p = 0.01), although it could not explain tachycardia during follow up.
In patients with SARS, cardiovascular complications including hypotension and tachycardia were common but usually self limiting. Bradycardia and cardiomegaly were less common, while cardiac arrhythmia was rare. However, only tachycardia persisted even when corticosteroid therapy was withdrawn.
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus‐specific treatments, and antiviral treatments should be useful in fighting COVID‐19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID‐19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID‐19 if the infection is uncontrollable. This article is protected by copyright. All rights reserved.
Background:
In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.
Methods:
We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.
Findings:
The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.
Interpretation:
2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.
Funding:
National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.
The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.
Telmisartan belongs to the angiotensin II type 1 (AT1) receptor antagonizing class of antihypertensives, which are widely recognized and increasingly prescribed because of their good tolerability. Moreover, due to the results of the ONTARGET trial program, telmisartan was the first AT1 receptor antagonist to receive approval for the prevention of cardiovascular events in cardiovascular high risk patients, thereby, indicating that its clinical importance will further increase.
This article reviews the pharmacokinetic and pharmacodynamic properties of telmisartan with a special focus on novel pharmacokinetic characteristics of the drug.
An overview of the published data regarding the pharmacokinetic properties of telmisartan as well as a summary of the results from selected small exploratory and large clinical outcome trials involving telmisartan.
Telmisartan is a safe and effective alternative for the treatment of hypertension. Moreover, due to its good tolerability, an increasing use of telmisartan in cardiovascular high risk patients can be anticipated. This will grant further experimental and clinical research on AT1 receptor-independent pharmacodynamics of telmisartan as well as on telmisartan-related drug safety issues.
Losartan potassium, an angiotensin II receptor antagonist, is the first of a new class of agents to be introduced for the treatment of hypertension. In this review, we describe the clinical pharmacology of losartan, including its pharmacokinetics in healthy, male volunteers and special patient groups, such as the elderly, patients with liver disease and patients with renal impairment. We also review its pharmacodynamics, including safety and tolerability; specificity of action; and the effect of salt depletion. We then review the studies examining clinical efficacy and safety in hypertension.
The renin-angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2-8)], Ang IV [Ang-(3-8)], and Ang-(1-7) may also have important biological activities. Ang-(1-7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1-7) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1-7) after an acute water load. Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1-7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1-7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.
The membrane-associated carboxypeptidase angiotensin-converting enzyme 2 (ACE2) is an essential regulator of heart function. Now, Li at al. identify and characterize an unexpected second function of ACE2 as a partner of the SARS-CoV spike glycoprotein in mediating virus entry and cell fusion.
The angiotensin-converting enzyme 2 (ACE2) is an important regulator of the renin-angiotensin system and was very recently identified as a functional receptor for the SARS virus. The ACE2 sequence is similar (sequence identities 43% and 35%, and similarities 61% and 55%, respectively) to those of the testis-specific form of ACE (tACE) and the Drosophila homolog of ACE (AnCE). The high level of sequence similarity allowed us to build a robust homology model of the ACE2 structure with a root-mean-square deviation from the aligned crystal structures of tACE and AnCE less than 0.5A. A prominent feature of the model is a deep channel on the top of the molecule that contains the catalytic site. Negatively charged ridges surrounding the channel may provide a possible binding site for the positively charged receptor-binding domain (RBD) of the S-glycoprotein, which we recently identified [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Several distinct patches of hydrophobic residues at the ACE2 surface were noted at close proximity to the charged ridges that could contribute to binding. These results suggest a possible binding region for the SARS-CoV S-glycoprotein on ACE2 and could help in the design of experiments to further elucidate the structure and function of ACE2.
The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homologue of the key regulator of blood pressure angiotensin-converting enzyme (ACE). Since its discovery in 2000, ACE2 has been implicated in heart function, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-(1-7). Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts.
Angiotensin-converting enzyme 2 (ACE2) is considered an important therapeutic target for controlling cardiovascular diseases and severe acute respiratory syndrome (SARS) outbreaks. Recently solved high-resolution crystal structures of the apo-bound and inhibitor-bound forms of ACE2 have provided the basis for a novel molecular docking approach in an attempt to identify ACE2 inhibitors and compounds that block SARS coronavirus spike protein-mediated cell fusion. In this study, approximately 140 000 small molecules were screened by in silico molecular docking. In this structure-activity relation study, the molecules with the highest predicted binding scores were identified and assayed for ACE2 enzymatic inhibitory activity and for their ability to inhibit SARS coronavirus spike protein-mediated cell fusion. This approach identified N-(2-aminoethyl)-1 aziridine-ethanamine as a novel ACE2 inhibitor that also is effective in blocking the SARS coronavirus spike protein-mediated cell fusion. Thus, the molecular docking approach resulting in the inhibitory capacity of N-(2-aminoethyl)-1 aziridine-ethanamine provides an attractive small molecule lead compound on which the development of more effective therapeutic agents could be developed to modulate hypertension and for controlling SARS infections.
Viruses frequently render cells refractory to subsequent infection with the same virus. This state of superinfection immunity counteracts potentially detrimental consequences for the infected cell and facilitates high-level replication and viral spread in the host.
Here, we show that human immunodeficiency virus (HIV) employs its early gene product Nef to efficiently interfere with superinfection at the viral-entry step. In this context, we identify the downregulation of cell-surface CCR5, the major HIV coreceptor, as a novel and highly conserved activity of Nef. Nef targets the CCR5 coreceptor and the HIV binding receptor CD4 via distinct cellular machineries to enhance the endocytosis rate of both HIV receptor components and to accelerate their degradation. Functionally, these genetically separable actions by Nef synergized to efficiently protect cells from HIV superinfection at the level of fusion of the viral envelope with the plasma membrane.
HIV has evolved two independent activities for Nef to downregulate the receptor complex and to facilitate its efficient replication and spread. This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis.
We investigated in Lewis normotensive rats the effect of coronary artery ligation on the expression of cardiac angiotensin-converting enzymes (ACE and ACE 2) and angiotensin II type-1 receptors (AT1a-R) 28 days after myocardial infarction. Losartan, olmesartan, or the vehicle (isotonic saline) was administered via osmotic minipumps for 28 days after coronary artery ligation or sham operation. Coronary artery ligation caused left ventricular dysfunction and cardiac hypertrophy. These changes were associated with increased plasma concentrations of angiotensin I, angiotensin II, angiotensin-(1-7), and serum aldosterone, and reduced AT1a-R mRNA. Cardiac ACE and ACE 2 mRNAs did not change. Both angiotensin II antagonists attenuated cardiac hypertrophy; olmesartan improved ventricular contractility. Blockade of the AT1a-R was accompanied by a further increase in plasma concentrations of the angiotensins and reduced serum aldosterone levels. Both losartan and olmesartan completely reversed the reduction in cardiac AT1a-R mRNA observed after coronary artery ligation while augmenting ACE 2 mRNA by approximately 3-fold. Coadministration of PD123319 did not abate the increase in ACE 2 mRNA induced by losartan. ACE 2 mRNA correlated significantly with angiotensin II, angiotensin-(1-7), and angiotensin I levels. These results provide evidence for an effect of angiotensin II blockade on cardiac ACE 2 mRNA that may be due to direct blockade of AT1a receptors or a modulatory effect of increased angiotensin-(1-7).
Rapid response: Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections—Novel mode of treatment. Response to the emerging novel coronavirus outbreak
- Phadke M.
Phadke, M., & Saunik, S. (2020). Rapid response: Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona
Virus infections-Novel mode of treatment. Response to the emerging
novel coronavirus outbreak. BMJ 2020, 368, m406. https://doi.org/
10.1136/bmj.m406
The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell‐surface CCR5 and CD4
- N. Michel
- I. Allespach
- S. Venzke
- O. T. Fackfmicheller
- O. T. Keppler