No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches
Abstract
Effective treatment choices to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited because of the absence of effective target-based therapeutics. The main object of the current research was to estimate the antiviral activity of cannabinoids (CBDs) against the human coronavirus SARS-CoV-2. In the presented research work, we performed in silico and in vitro experiments to aid the sighting of lead CBDs for treating the viral infections of SARS-CoV-2. Virtual screening was carried out for interactions between 32 CBDs and the SARS-CoV-2 Mpro enzyme. Afterward, in vitro antiviral activity was carried out of five CBDs molecules against SARS-CoV-2. Interestingly, among them, two CBDs molecules namely Δ (Yu et al., 2020 [9])-tetrahydrocannabinol (IC50 = 10.25 μM) and cannabidiol (IC50 = 7.91 μM) were observed to be more potent antiviral molecules against SARS-CoV-2 compared to the reference drugs lopinavir, chloroquine, and remdesivir (IC50 ranges of 8.16–13.15 μM). These molecules were found to have stable conformations with the active binding pocket of the SARS-CoV-2 Mpro by molecular dynamic simulation and density functional theory. Our findings suggest cannabidiol and Δ (Yu et al., 2020 [9])-tetrahydrocannabinol are possible drugs against human coronavirus that might be used in combination or with other drug molecules to treat COVID-19 patients.
... Thus, further research studies could be conducted based on this novel finding to develop prevention approaches for COVID-19 as well as other viral infections which exploit ACE2 receptors as a molecular gateway (Wang et al. 2020). Raj et al. (2020) have suggested that -9-THC and CBD are possible drugs against SARS-CoV-2. The experiments were performed in vitro and in silico to observe interactions between cannabinoids and the SARS-CoV-2 main protease (M pro ). ...
... The two cannabinoids, -9-THC and CBD, are found to form stable binding with M pro , inhibiting M pro -mediated translation, and protein maturation. From the dose-response curve analysed by immunofluorescence, -9-THC and CBD with the 50% viral inhibitory concentration (IC 50 ) of 10.25 μmol L −1 and 7.91 μmol L −1 , respectively, were found to be stronger antiviral compounds against human coronavirus compared with the reference antiviral drugs Remdesivir, Chloroquine and Lopinavir (Raj et al. 2020). Although Remdesivir could reduce the death rate of COVID-19 patients, subpleural inflammatory infiltrates in the lungs can still occur (Williamson et al. 2020). ...
... A reduction of lung function can continue even after recovery. Hence, two major cannabinoids, especially CBD, the one that has no psychoactive effects, could be added as an adjunct to the antiviral drugs against SARS-CoV-2 to inhibit the SARS-CoV-2 M pro , which leads to blocking the translation process and also act as agonists of CB-2 receptor to reduce proinflammatory cytokine levels in lung cells (Raj et al. 2020). ...
Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries. The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties. Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication. Apart from cannabinoids, terpenes in cannabis plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.
... In addition, several natural products have been found that can block SARS-CoV-2 cell entry, including luteolin and CBDA [16,17]. Cannabis has recently been proposed as a potential COVID-19 inhibitor based on the bioactive substances it contains, such as CBD and THC [18]. Cannabis sativa L. has long been valued as a food, dietary fiber, nutritious oil, and medical source throughout Europe and Africa, especially in traditional Chinese medicine. ...
... Their docking score was higher than that of luteolin-binding ACE2, −5.23 kcal/mol [15]. Compared to coumarin derivatives [44], the docking score of these three small molecules was all lower but higher than that of other cannabinoids [18]. ...
... CBGVA formed two conventional H bonds with Gly496 and Asn501, as well as four pi-alkyl bonds with Tyr453, Tyr495, and Tyr505, which was identical to the KC interaction with ACE2 [45], and one Pi-Pi bond with Tyr505 ( Figure 1C). The previous study showed that CBD and CBN formed two and one H bonds, respectively, at the Glu166 and Met165 sites [18]. This differed from that of CBNA; even CBN and CBNA had very similar structures. ...
Despite the approval of multiple vaccinations in different countries, the majority of the world’s population remains unvaccinated due to discrepancies in vaccine distribution and limited production capacity. The SARS-CoV-2 RBD-ACE2 complex (receptor binding domain that binds to ACE2) could be a suitable target for the development of a vaccine or an inhibitor. Various natural products have been used against SARS-CoV-2. Here, we docked 42 active cannabinoids to the active site of the SARS-CoV-2 and SARS-CoV complex of RBD-ACE2. To ensure the flexibility and stability of the complex produced after docking, the top three ligand molecules with the best overall binding energies were further analyzed through molecular dynamic simulation (MDS). Then, we used the webserver Swissadme program and binding free energy to calculate and estimate the MMPBSA and ADME characteristics. Our results showed that luteolin, CBGVA, and CBNA were the top three molecules that interact with the SARS-CoV-2 RBD-ACE2 complex, while luteolin, stigmasterol, and CBNA had the strongest contact with that SARS-CoV. Our findings show that luteolin may be a potential inhibitor of infections caused by coronavirus-like pathogens such as COVID-19, although further in vivo and in vitro research is required.
... In addition, it is possible that individuals who smoke or vape cannabis are more likely to become infected because of associated risky behaviors, including increased contact between the fingers and the mouth, removal of one's mask while vaping or smoking and/or sharing cannabis products with others who are infected. Conversely, cannabis products may have pharmacological effects that might offer some protection against SARS-CoV-2 infection [20][21][22][23]. For example, some cannabinoids can bind to the SARS-CoV-2 spike protein that is critical for viral entry into cells [24]. ...
... For example, some cannabinoids can bind to the SARS-CoV-2 spike protein that is critical for viral entry into cells [24]. Cannabidiol (CBD) may down-regulate angiotensin converting enzyme 2 (ACE2), which is the site of SARS-CoV-2 viral attachment on cell surfaces, and inhibits viral replication in pulmonary epithelial cells [20,22]. ...
... Structural-based screening of cannabinoids found that THC and CBD bind stably to SARS-CoV-2 M pro , a critical enzyme in the life cycle of the virus; and these cannabinoids inhibit viral replication in vitro [22]. ...
Background and aims:
Cannabis use is increasingly common among pregnant individuals and might be a risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to test whether prenatal cannabis use is associated with increased risk of SARS-CoV-2 infection during pregnancy.
Design:
Retrospective cohort study.
Setting:
California USA.
Participants:
58,114 pregnancies (with outcomes from 3/5/2020 to 9/30/2021) among 57,287 unique pregnant women aged 14-54 years who were screened for prenatal substance use, enrolled in Kaiser Permanente Northern California (KPNC) (a healthcare system), and had not tested positive for COVID-19 prior to pregnancy onset.
Measurements:
We utilized data from the KPNC electronic health record. Cannabis use status (current, recently quit, non-user) was based on universal screenings during prenatal care (including ≥1 urine toxicology test and self-reported use on a self-administered questionnaire). SARS-CoV-2 infection (based on polymerase chain reaction (PCR) tests) was estimated in time-to-event analyses using Cox proportional hazard regression models adjusting for covariates. Secondary analyses examined differences in a) SARS-CoV-2 positivity testing rates and b) SARS-CoV-2 infection rates among those tested.
Findings:
We observed 348,810 person-months of follow-up time in our cohort with 41,064 SARS-CoV-2 PCR tests, and 6% (n=2,414) of tests being positive. At the start of follow-up, 7% of pregnant individuals had current use, 12% had recently quit, and 81% did not use cannabis. Adjusting for covariates, current use was associated with lower rates of SARS-CoV-2 infection (adjusted hazard ratio [aHR]=0.60,95% confidence interval [CI]:0.49-0.74) than non-use. Those who had recently quit did not differ from non-cannabis users in infection rates (aHR=0.96,95%CI:0.86-1.08). Sensitivity analyses among patients who received a SARS-CoV-2 test also found lower odds of infection associated with current versus no cannabis use (aOR=0.76,CI:0.61-0.93).
Conclusions:
Current cannabis use appears to be associated with a reduced risk of severe acute respiratory syndrome coronavirus 2 infection among pregnant individuals.
... Notably, published pre-clinical studies support bioactive compounds including cannabinoids from the Cannabis species may exert promising antiviral effects [20,21]. For instance, virtual screening has identified five hits with strong binding energies with substrate-binding site of SARS-CoV-2 M pro from a panel of 32 cannabinoids [22]. Further in vitro studies have revealed that ∆ 9 -tetrahydrocannabinol (∆ 9 -THC) and cannabinol are potent inhibitors against SARS-CoV-2 M pro with IC 50 values of 10.25 and 7.91 µM, respectively [22]. ...
... For instance, virtual screening has identified five hits with strong binding energies with substrate-binding site of SARS-CoV-2 M pro from a panel of 32 cannabinoids [22]. Further in vitro studies have revealed that ∆ 9 -tetrahydrocannabinol (∆ 9 -THC) and cannabinol are potent inhibitors against SARS-CoV-2 M pro with IC 50 values of 10.25 and 7.91 µM, respectively [22]. Additionally, an in silico study reported that cannabinoids including cannabichromanon, cannabinolic acid, and cannabinol had a free binding ∆G of −33.63, −23.24, and −21.60 kcal/mol, respectively, at the active site of SARS-CoV-2 M pro [23]. ...
... Apart from the virus spike protein and ACE2, the 3CL M pro is also a critical molecular target for the prevention of the replication of SARS-CoV-2. The anti-M pro potential of a handful of cannabinoids including ∆ 9 -THCA, ∆ 9 -THC, CBN, CBD and CBDA was studied using in silico methods (by molecular dynamic simulation and docking) [22]. However, the understanding of minor cannabinoids' effects on the SARS-CoV-2 3CL M pro is limited by some shortcomings, such as a lack of experimental evidence and a confined selection of minor cannabinoids. ...
The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (Mpro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 Mpro, their anti-Mpro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-Mpro activity using a biochemical assay. Additionally, the binding affinities and molecular interactions between the active cannabinoids and the Mpro protein were studied by a biophysical technique (surface plasmon resonance; SPR) and molecular docking, respectively. Cannabinoids tetrahydrocannabutol and cannabigerolic acid were the most active Mpro inhibitors (IC50 = 3.62 and 14.40 μM, respectively) and cannabigerolic acid had a binding affinity KD=2.16×10−4 M). A preliminary structure and activity relationship study revealed that the anti-Mpro effects of cannabinoids were influenced by the decarboxylation of cannabinoids and the length of cannabinoids’ alkyl side chain. Findings from the biochemical, biophysical, and computational assays support the growing evidence of cannabinoids’ inhibitory effects on SARS-CoV-2 Mpro.
... There is evidence, albeit limited, that cannabidiol (CBD) may have potential as an anti-SARS-CoV-2 agent [48,[67][68][69][70][71] presented concomitantly with important warnings against prescription of cannabinoid products for COVID-related symptoms at present [50,72]. For example, CBD has been suggested to be an efficient inhibitor of SARS-CoV-2 (strain 229E) replication in human lung fibroblasts (MRC-5) through enhancement of antiviral terpene efficacy [68]. ...
... For example, CBD has been suggested to be an efficient inhibitor of SARS-CoV-2 (strain 229E) replication in human lung fibroblasts (MRC-5) through enhancement of antiviral terpene efficacy [68]. Both THC and CBD have been reported to interact with the Mpro protein of SARS-CoV-2 and to exhibit anti-SARS-CoV-2 activities with an IC50 of 10.25 µM and 7.91 µM, respectively [48]. Moreover, Esposito et al. [69] have hypothesized that CBD may have some adjunctive anti-COVID efficacy, as CBD administration can down-regulate the expression of SARS-CoV2 receptors (ACE2, transmembrane proteinase 2 [TMPRSS2]) in 3D human epithelial tissue models, as initially reported by Wang et al. [70]. ...
... The summary of evidence suggesting that CBG may represent a lead antimicrobial cannabinoid is illuminating [12]. Further, there is a pressing interest in the potential of cannabinoids, such as CBD, to inhibit SARS-CoV-2 cellular entry and replication through varying mechanisms [48,49,101]. This review augments these prior articles by focusing on the most recent literature on cannabis-related antimicrobials, primarily summarized in Tables 1-5, and providing a synopsis of the knowledge gaps that act as a barrier to the acceptance and utility of cannabinoid-based antimicrobial therapeutics. ...
Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP–microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.
... It can also be found in peripheral organs, such as the liver, muscles and pancreas, and in adipose tissue, where it regulates food intake, energy expenditure and reward-related responses [1]. The CB2 receptor is highly expressed in immune cells, such as lymphocytes B, lymphocytes CD8, NK cells, monocytes, lymphocytes CD4 and neutrophils [5,6]. CB2 receptors present an anti-inflammatory effect by reducing the re-lymphocytes CD4 and neutrophils [5,6]. ...
... The CB2 receptor is highly expressed in immune cells, such as lymphocytes B, lymphocytes CD8, NK cells, monocytes, lymphocytes CD4 and neutrophils [5,6]. CB2 receptors present an anti-inflammatory effect by reducing the re-lymphocytes CD4 and neutrophils [5,6]. CB2 receptors present an anti-inflammatory effect by reducing the release of proinflammatory cytokines, increasing production of antiinflammatory cytokines, inhibiting macrophage migration and regulating lymphocyte T activation [5]. ...
... CB2 receptors present an anti-inflammatory effect by reducing the re-lymphocytes CD4 and neutrophils [5,6]. CB2 receptors present an anti-inflammatory effect by reducing the release of proinflammatory cytokines, increasing production of antiinflammatory cytokines, inhibiting macrophage migration and regulating lymphocyte T activation [5]. ...
The COVID-19 pandemic caused by the SARS-CoV-2 virus made it necessary to search for new options for both causal treatment and mitigation of its symptoms. Scientists and researchers around the world are constantly looking for the best therapeutic options. These difficult circumstances have also spurred the re-examination of the potential of natural substances contained in Cannabis sativa L. Cannabinoids, apart from CB1 and CB2 receptors, may act multifacetedly through a number of other receptors, such as the GPR55, TRPV1, PPARs, 5-HT1A, adenosine and glycine receptors. The complex anti-inflammatory and antiviral effects of cannabinoids have been confirmed by interactions with various signaling pathways. Considering the fact that the SARS-CoV-2 virus causes excessive immune response and triggers an inflammatory cascade, and that cannabinoids have the ability to regulate these processes, it can be assumed that they have potential to be used in the treatment of COVID-19. During the pandemic, there were many publications on the subject of COVID-19, which indicate the potential impact of cannabinoids not only on the course of the disease, but also their role in prevention. It is worth noting that the anti-inflammatory and antiviral potential are shown not only by well-known cannabinoids, such as cannabidiol (CBD), but also secondary cannabinoids, such as cannabigerolic acid (CBGA) and terpenes, emphasizing the role of all of the plant’s compounds and the entourage effect. This article presents a narrative review of the current knowledge in this area available in the PubMed, Scopus and Web of Science medical databases.
... CBD can bind to SARS-CoV-2Mpro by blocking its transcription, and CBD can interact as an agonist of the CB2 receptor. These two activities can reduce the secretion of pro-inflammatory cytokines in lung cells (27). ...
... The SARS-CoV-2Mpro downregulation is not associated with side effects in humans and remains at this stage as one the best molecular targets for decreasing the coronavirus replication (37,38). Thus, CBD, by acting as an agonist of the CB2 receptor, can decrease the activity of SARS-CoV-2Mpro and can downregulate the viral replication due to its binding affinity (27). At this date, SARS CoV-2Mpro inhibitors are not toxic in humans (26). ...
... Moreover, the drug-drug interactions between CBD and other treatments are required to be investigated in COVID-19 patients, and at this stage a lack of studies remains still present. A recent study has shown that CBD could be a stronger antiviral agent than other drugs, such as lopinavir and remdesivir (27). Nevertheless, there are few research articles which highlight the potential action of CBD on cytokine storm in COVID-19. ...
Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/β-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/β-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.
... One study from showed the downregulation of hACE2 from CBD extract high content [28]. Another study is the first and only study from Raj et al. (2021) that reported the direct and remarkably activity of THC, CBD, and CBN against SARS-CoV2 infection with the same potency as the standard drugs such as chloroquine, remdesivir, and lopinavir in the cell-based assay [29]. However, the mechanism of action of these three cannabinoids against SARS-CoV2 infection is not yet known for certain. ...
... One study from showed the downregulation of hACE2 from CBD extract high content [28]. Another study is the first and only study from Raj et al. (2021) that reported the direct and remarkably activity of THC, CBD, and CBN against SARS-CoV2 infection with the same potency as the standard drugs such as chloroquine, remdesivir, and lopinavir in the cell-based assay [29]. However, the mechanism of action of these three cannabinoids against SARS-CoV2 infection is not yet known for certain. ...
... The antiviral activity of THC, CBD, and CBN against SARS-CoV2 infection was recently reported from a cell-based assay, but still the mechanism of action of mentioned cannabinoids has not yet been elucidated [29]. Currently, only the predicted mechanism was proposed by a computational experiment [29,30]. ...
... In vitro activity of THC and CBD against SARS-CoV-2 was determined (Table 5) following an interaction study involving an in silico experiment between 32 cannabinoids and SARS-CoV-2 M pro [189]. CBD was characterized as a PPARγ agonist, so likely can exert antiviral activity and suppress the onset of the cytokine storm in COVID-19 infection, regulate fibroblast/myofibroblast activation and inhibit the development of pulmonary fibrosis, resulting in an amelioration of lung function in recovered patients [168]. ...
... Computational studies such as docking scores, molecular dynamic (MD) simulation and density functional theory (DFT) showed that THC and CBD had stable conformations with the binding pocket of the M pro enzyme [189]. The THC moiety and its derivatives have good stability and higher binding affinity in their complex with SARS-CoV-2 M pro compared to a complex of hydroxychloroquine, remdesivir and their derivatives [190]. ...
... The THC moiety and its derivatives have good stability and higher binding affinity in their complex with SARS-CoV-2 M pro compared to a complex of hydroxychloroquine, remdesivir and their derivatives [190]. A HOMO-LUMO energy gap study also showed a good stability profile of THC and CBD with the SARS-CoV-2 M pro enzyme [189]. It is notable that human proteases such as SARS-CoV-2 M pro have not been reported with similar cleavage specificity, so inhibitors of this enzyme should not be toxic [163]. ...
Abstract: Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coron-avirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.
... One study from showed the downregulation of hACE2 from CBD extract high content [28]. Another study is the first and only study from Raj et al. (2021) that reported the direct and remarkably activity of THC, CBD, and CBN against SARS-CoV2 infection with the same potency as the standard drugs such as chloroquine, remdesivir, and lopinavir in the cell-based assay [29]. However, the mechanism of action of these three cannabinoids against SARS-CoV2 infection is not yet known for certain. ...
... One study from showed the downregulation of hACE2 from CBD extract high content [28]. Another study is the first and only study from Raj et al. (2021) that reported the direct and remarkably activity of THC, CBD, and CBN against SARS-CoV2 infection with the same potency as the standard drugs such as chloroquine, remdesivir, and lopinavir in the cell-based assay [29]. However, the mechanism of action of these three cannabinoids against SARS-CoV2 infection is not yet known for certain. ...
... The antiviral activity of THC, CBD, and CBN against SARS-CoV2 infection was recently reported from a cell-based assay, but still the mechanism of action of mentioned cannabinoids has not yet been elucidated [29]. Currently, only the predicted mechanism was proposed by a computational experiment [29,30]. ...
THC, CBD, and CBN were reported as promising candidates against SARS-CoV2 infection, but the mechanism of action of these three cannabinoids is not understood. This study aims to determine the mechanism of action of THC, CBD, and CBN by selecting two essential targets that directly affect the coronavirus infections as viral main proteases and human angiotensin-converting enzyme2. Tested THC and CBD presented a dual-action action against both selected targets. Only CBD acted as a potent viral main protease inhibitor at the IC50 value of 1.86 ± 0.04 µM and exhibited only moderate activity against human angiotensin-converting enzyme2 at the IC50 value of 14.65 ± 0.47 µM. THC acted as a moderate inhibitor against both viral main protease and human angiotensin-converting enzymes2 at the IC50 value of 16.23 ± 1.71 µM and 11.47 ± 3.60 µM, respectively. Here, we discuss cannabinoid-associated antiviral activity mechanisms based on in silico docking studies and in vitro receptor binding studies.
... CB2 (peripheral type) is expressed mainly on the immune system cells [30][31][32]. CB2 is involved in the implementation of the anti-inflammatory effect via reducing the production of proinflammatory cytokines and increasing the production of antiinflammatory cytokines [33]. CB2 agonists inhibit recruitment of leukocytes and reduce the content of tumor necrosis factor-alpha (TNF-α), interleukins (IL-1β, IL-6, IL-18), monocyte chemoattractant protein-1 (MCP-1) and active forms of oxygen [31]. ...
... Some studies demonstrated high potential of cannabinoids in the treatment of systemic respiratory infection [33]. For example, CB2 activation limited the infiltration of immune cells into the lungs of animals infected with respiratory syncytial virus and reduced the number of neutrophils and monocytes in the bronchoalveolar lavage. ...
Publication interest in cannabinoids, including phytocannabinoids, endogenous cannabinoids, synthetic cannabinoids and cannabinomimetic compounds, is due to the therapeutic potential of these compounds in inflammatory pathology. Since recent years, scientific interest was focused on compounds with cannabinomimetic activity. The therapeutic use of phytocannabinoids and endocannabinoids is somewhat limited due to unresolved issues of dosing, toxicity and safety in humans, while cannabinoid-like compounds combine similar therapeutic effects with a high confirmed safety. Targets for endocannabinoids and phytocannabinoids are endocannabinoid receptors 1 and 2, G protein-coupled receptors (GPCRs), peroxisome proliferator-activated receptors (PPARs), and transient receptor potential ion channels (TRPs). Non-endocannabinoid N-acylethanolamines do not interact with cannabinoid receptors and exhibit agonist activity towards non-cannabinoid receptors, such as PPARs, GPCRs and TRPs. This literature review includes contemporary information on the biological activity, metabolism and pharmacological properties of cannabinoids and cannabinoid-like compounds, as well as their receptors. We established that only a few studies were devoted to the relationship of non-endocannabinoid N-acylethanolamines with non-cannabinoid receptors, such as PPARs, GPCRs, and also with TRPs. We have focused on issues that were insufficiently covered in the published sources in order to identify gaps in existing knowledge and determine the prospects for scientific research.
... On the other hand, in silico analysis suggests that CBD binds to the S1 virus membrane protein by interactions with the residues Q189, M165 and E16, causing an inhibitory effect with an IC 50 of 7.91 µM [104]. On the other hand, ACE2 expression in the epithelium is high in males, older people and smokers, evidencing the risk of the population to the expression of the ACE2 receptor [105]. ...
... Viral proteins and RNA from the virus genome accumulate, forming virons in the endoplasmic reticulum and the Golgi apparatus and are then transported in vesicles to the extracellular space [104]. In this process, proinflammatory M1 macrophages and helper T cells secrete interleukins, which produce inflammation within lung cells. ...
Cannabis sativa is one of the first medicinal plants used by humans. Its medical use remains controversial because it is a psychotropic drug whose use has been banned. Recently, however, some countries have approved its use, including for recreational and medical purposes, and have allowed the scientific study of its compounds. Cannabis is characterized by the production of special types of natural products called phytocannabinoids that are synthesized exclusively by this genus. Phytocannabinoids and endocannabinoids are chemically different, but both pharmacologically modulate CB1, CB2, GRP55, GRP119 and TRPV1 receptor activities, involving activities such as memory, sleep, mood, appetite and motor regulation, pain sensation, neuroinflammation, neurogenesis and apoptosis. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids with greater pharmacological potential, including anti-inflammatory, neuroprotective and anticonvulsant activities. Cannabidiol is showing promising results for the treatment of COVID-19, due to its capability of acting on the unleashed cytokine storm, on the proteins necessary for both virus entry and replication and on the neurological consequences of patients who have been infected by the virus. Here, we summarize the latest knowledge regarding the advantages of using cannabinoids in the treatment of COVID-19.
... Table 3 (Ref. [5,6,8,16,22,[37][38][39][40][41][42][43][44][45]) shows the 29 unique drugs involved in these interactions. A subset of these results that met the threshold of 0.99 shown in Table 4 (Ref. ...
... A subset of these results that met the threshold of 0.99 shown in Table 4 (Ref. [5,6,8,22,34,38,41,44]) was separated, which yielded 44 DTIs involving 13 unique drugs with a 99% probability of interaction with their respective proteins. ...
Background:
In the current COVID-19 pandemic, with an absence of approved drugs and widely accessible vaccines, repurposing existing drugs is vital to quickly developing a treatment for the disease.
Methods:
In this study, we used a dataset consisting of sequences of viral proteins and chemical structures of pharmaceutical drugs for known drug-target interactions (DTIs) and artificially generated non-interacting DTIs to train a binary classifier with the ability to predict new DTIs. Random Forest (RF), deep neural network (DNN), and convolutional neural networks (CNN) were tested. The CNN and RF models were selected for the classification task.
Results:
The models generalized well to the given DTI data and were used to predict DTIs involving SARS-CoV-2 nonstructural proteins (NSPs). We elucidated (with the CNN) 29 drugs involved in 82 DTIs with a 97% probability of interaction, 44 DTIs of which had a 99% probability of interaction, to treat COVID-19. The RF elucidated 6 drugs involved in 17 DTIs with a 90% probability of interacting.
Conclusions:
These results give new insight into possible inhibitors of the viral proteins beyond pharmacophore models and molecular docking procedures used in recent studies.
... There are some lines of evidence for an anti-viral activity of phytocannabinoids [60,264]. Some phytocannabinoids, especially ∆ 9 -THC and CBD, bind to the M pro protease of SARS-CoV-2, which plays a role in viral replication [60,264]. ...
... There are some lines of evidence for an anti-viral activity of phytocannabinoids [60,264]. Some phytocannabinoids, especially ∆ 9 -THC and CBD, bind to the M pro protease of SARS-CoV-2, which plays a role in viral replication [60,264]. CBGA and CBDA were found to be allosteric and orthosteric ligands for the spike protein of SARS-CoV-2 and prevented infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein [265]. ...
Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... 14 Moreover, CBD has potential antiviral properties. 2,4,5,15 Recently, in vitro and in silico analysis suggested that in VERO cells, CBD reduces intracellular expression of the spike protein S of the SARS-CoV-2. 15 CBD showed anxiolytic and antidepressant effects in pre-clinical [16][17][18] and clinical 19,20 studies. ...
... 2,4,5,15 Recently, in vitro and in silico analysis suggested that in VERO cells, CBD reduces intracellular expression of the spike protein S of the SARS-CoV-2. 15 CBD showed anxiolytic and antidepressant effects in pre-clinical [16][17][18] and clinical 19,20 studies. It could also improve burnout syndrome symptoms and other mental health outcomes in health care workers treating COVID-19 patients. ...
Importance: Owing to its anti-inflammatory properties and antiviral "in vitro" effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19). Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19. Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil. Setting: Patients were recruited in an emergency room. Participants: Block randomized patients (1:1 allocation ratio-by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study. Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days. Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment. Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD (n=49) or in placebo (n=42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity (χ2=0.025, p=0.988) and median time to symptom resolution (12 days [95% confidence interval, CI, 6.5-17.5] in the CBD group, 9 days [95% CI, 4.8-13.2] in the placebo group [χ2=1.6, p=0.205 by log-rank test]). By day 28, 83.3% in the CBD group and 90.2% in the placebo group had resolved symptoms. There were no between-group differences on secondary measures. CBD was well tolerated, producing mostly mild and transient side effects (e.g., somnolence, fatigue, changes in appetite, lethargy, nausea, diarrhea, and fever), with no significant differences between CBD and placebo treatment groups. Conclusions and Relevance: Daily administration of 300 mg CBD for 14 days failed to alter the clinical evolution of COVID-19. Further trials should explore the therapeutic effect of CBD in patients with severe COVID-19, possibly trying higher doses than the used in our study. Trial Registration: ClinicalTrials.gov identifier NCT04467918 (date of registration: July 13, 2020).
... There are interesting reports on cannabinoids from Cannabis Sativa for their anti-covid-19 properties. To date these studies have mostly been restricted to cellular-based in vitro studies (Raj et al., 2021). The most potent anti-viral properties were shown by tetrahydrocannabinol (THC) and cannabindiol (CBD) compared to the reference drugs lopinavir and remdesvir. ...
There appear to be huge variations and aberrations in the reported data in COVID-19 two years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms, and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.
... In this case, CBD inhibits SARS-CoV-2 replication in the early stages of the disease. This relationship is therefore indicated by Nguyen et al. as a very effective potential measure to prevent infection in the early stages of infection; however, further testing and clinical trials are needed to clearly confirm the effects of cannabidiol on this virus [97,98]. ...
In collaboration with the MDPI publishing house, we are pleased to introduce the
reader to our new project, the Special Issue entitled “Advanced Eco-friendly Wood-Based Composites”. This Special Issue provides an opportunity to investigate the advanced ecofriendly wood-based composites from a broader perspective. The coronavirus pandemic and shutdown measures employed to contain it, as well as the ongoing war, have influenced and decelerated the world economy and adversely impacted the research activities on most levels in all countries. Surprisingly, researchers in the field of wood-based composites have continued to make progress, which is also described in this Special Issue.
... Many studies have used molecular modeling to investigate the possibilities of countering COVID-19 infection using active ingredients obtained from natural sources. A recent in silico study 22 was conducted on certain cannabinoids using the SARS-CoV-2 Mpro (main protease) enzyme as the main target, followed by in vitro antiviral activity against SARS-CoV-2. Δ9-tetrahydrocannabinol and cannabidiol (CBD) showed the most significant antiviral potential, displaying IC50 values of 10.25 and 7.91 μM, respectively, which were comparable to those of lopinavir, chloroquine, and remdesivir, with IC50 values ranging between 8.16 and 13.15 μM. ...
The emergence of a novel coronavirus that later on rendered a global pandemic, caused desperation within the communities and drove increased interest in exploring medicinal plant-based therapeutics to treat and prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections. Many medicinal plants have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects that hinder, cure, or ease the symptoms of COVID-19 infection. This exploratory study seeks to dock the active components of Cannabis sativa, a natural plant with several pharmacological and biological properties, with the angiotensin-converting enzyme II (ACE2) receptor. A total of 3 C. sativa active components have been found to bind to the ACE2 protein active site and could inhibit spike binding, although they do not compete directly with the receptor-binding domain (RBD) of SARS-CoV-2. 6-Prenylapigenin, cannabivarin (CBN-C3), and Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA) have a greater affinity (-8.3, -8.3, and -8.0 kcal/mol, respectively) and satisfactory interaction with ACE2 than its inhibitor MLN-4760 (-7.1 kcal/mol). These potential drugs with higher affinity for the ACE2 receptor and adequate absorption, distribution, metabolism, excretion, and toxicity (ADMET) values are candidates for treating or preventing SARS-CoV-2 infections. In vitro and in vivo investigations are needed to evaluate further the efficacy and toxicity of these hit compounds.
... [440][441][442] Raj et al. screened 32 cannabinoids with binding affinity to SARS-CoV-2 M pro . 443 Five cannabinoids were selected, and their antiviral abilities were tested in vitro. Cannabidiol (IC 50 = 7.91 μM) was found to be exert more potent antiviral effects against SARS-CoV-2 in vitro compared to the reference drugs lopinavir, chloroquine, and remdesivir (IC 50 ranges of 8.16-13.15 ...
The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and M pro , interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.
... In this experiment, the best dock complex of INS-SD, SLS, and SDBS complexes were submitted for MD simulation using Yasara dynamic software on LG Intel Core i5-CPU with enterprise version (64-bit), respectively. The previously reported protocol was adopted with minor modifications to the MD simulation of the INS-SD, SLS, and SDBS complexes [23,24]. Briefly, the periodic cell boundaries were defined according to the complex size, and the water solvent was filled at 0.997 g/L density. ...
To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.
... Using the proper in silico tool, researchers can reduce time, effort, and resources consumption in the journey of drug discovery [62,63]. To gain a better understanding of the mode of action of novel compounds as antiviral and guide further SAR studies, we proceeded to examine the interaction of the most potent pyranopyrazole derivative with the SARS-CoV-2 M pro protein target. ...
COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV Mpro target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC50 values of 2.01, 1.83, and 4.60 μM respectively compared with 12.85 and 82.17 μM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 Mpro. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 Mpro and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.
... Compounds and drugs that act to satisfy mainly the first need of the three ones are relatively few to date. Of them, only nucleoside analogs/derivatives (NAs/NDs) and polyphenolics (PPhs) have shown significant successful progress as coronaviral-2 inhibitors (Mahase, 2021;Imran et al., 2021;Moirangthem and Surbala, 2021;Yan and Muller, 2020;Brunotte et al., 2021;Rabie, 2022aRabie, , 2022bCai et al., 2020;Rabie, 2021cRabie, , 2021dRaj et al., 2022Raj et al., , 2021. NAs are naturally more promising and highly biotolerated as antiviral therapeutics . ...
Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19) arisen by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At the same time, the appearance of a new strain of SARS-CoV-2, the Omicron variant, necessitates multiplied efforts in fighting COVID-19. Counteracting the crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) jointly altogether using the same inhibitor is a quite successful new plan to demultiplicate SARS-CoV-2 particles and eliminate COVID-19 whatever the SARS-CoV-2 subtype is (due to the significant conservation nature of RdRps and ExoNs in the different SARS-CoV-2 strains). Successive in silico screening of know NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode. Further in vitro evaluations affirmed the anti-SARS-CoV-2/anti-COVID-19 potentials of these NAs, with riboprine and forodesine being at the top. The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the coronaviral-2 polymerase/exoribonuclease interactions with RNA nucleotides in the SARS-CoV-2 Omicron variant (BA.5 sublineage) and accordingly alleviate COVID-19 infections, motivating us to initiate the two drugs' diverse anti-COVID-19 pharmacological evaluations to add both of them betimes in the COVID-19 therapeutic protocols.
... The TLR-4 protein and rutin molecule was placed at the center of the cubic box, adding the counterion to adjust the pH to the physiological level (i.e., 7.4) [36]. The simulation was commenced for 150 ns with a 2.5 fs time step at a constant temperature and pressure (NPT ensemble) [37]. A pre-established macro script (md run.mcr) ...
Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signal-ing, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydropho-bic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin's greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation , and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood-brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited Citation: Khan, A.; Khan, S.U.; Khan, A.; Shal, B.; Sabih-Ur-Rehman; Shaheed-Ur-Rehman; Htar, T.T.; Khan, S.; Anwar, S.; Alafnan, A.; Rengasamy, K.R. Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plants Compounds by Targeting
... Mpro is present among coronaviruses, with various Mpro substrates in various coronaviruses possessing common features. SARS-CoV-2 Mpro forms 12 non-structural proteins, including Nsp4 and Nsp16, via the cleavage of viral polyproteins, comprising RNA-dependent RNA polymerase (RdRp, Nsp12), as well as the helicase Nsp13 [13][14][15]. COVID-19 infection depends upon host cell factors, such as angiotensin-converting enzyme 2 (ACE2). The entrance of coronaviruses to the host cell is accommodated by the tight binding of the virus spike (S) proteins to the cell receptors that enhance viral entrance and adherence to the cell surface that subsequently results in the infection. ...
Cannabis sativa L. is an annual herbaceous plant that belongs to the family Cannabinaceae. In this study, the potential use of forty-five cannabinoids, previously identified from Cannabis sativa to alleviate COVID-19 infection via prohibition of crucial SARS-CoV-2 proteins using molecular docking, was examined. In silico studies were performed on three vital enzymes that serve as principle therapeutic targets to prevent SARS-CoV-2 replication. These enzymes are the main protease SARS-CoV-2 MPro, papain-like protease SARS-CoV-2 PLpro and angiotensin-converting enzyme 2 (ACE2). Regarding SARS-CoV-2 MPro, cannabichromanon (32) showed the best fitting within its active centers, followed by cannabinolic acid (22) and cannabinol (21), displaying ∆G of −33.63, −23.24, and −21.60 kcal/mol, respectively. Concerning SARS-CoV-2 PLpro, cannabichromanon (32) followed by cannabinolic acid (22) and cannabicyclolic acid (41) revealed the best binding within its active pockets owing to multiple bond formation with ∆G values of −28.36, −22.81, and −19.89 kcal/mol. Furthermore, cannabichromanon (32), cannabinolic acid (22), and cannabinol (21) showed considerable fitting within the active sites of angiotensin-converting enzyme 2 (ACE2) evidenced by their significant ∆G values that were estimated as −41.77, −31.34, and −30.36 kcal/mol, respectively. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) evaluation was performed on the tested cannabinoids to further explore their pharmacokinetics, pharmacodynamics, and toxicity properties. The results indicated the considerable pharmacokinetic, pharmacodynamic, and toxicity properties of cannabinol (21), cannabinolic acid (22), cannabichromanon (32), and cannabicyclolic acid (41) that showed best fitting scores within the active sites of the tested enzymes. Multivariate data analysis revealed that cannabichromanon and cannabinolic acid showed a discriminant nature and hence can be incorporated in pharmaceutical dosage forms to alleviate COVID-19 infection.
... Despite this evidence, there is still a lack of studies dedicat-ed exclusively to clarifying the mechanism of action affecting both the anti-inflammatory level and cannabinoids used for possible injuries in the CNS caused by SARS-CoV-2 [151]. Raj et al., 2020, tested in silico the antiviral effectiveness of CBD [152] and found that among other cannabinoids, CBD presented good antiviral activity. They also showed that CBD in cultured Vero cells infected with SARS-CoV-2 exhibited an IC50 value of 8 M for its inhibitory effect. ...
The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established, however, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, and indirect mechanisms of inflammatory / autoimmune origin. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potential promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review we address the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a decrease in viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.
... Cannabidiol (26) and Δ9-tetrahydrocannabinol (27) isolated from the plant showed more potency against SARS-CoV-2 virus compared to the reference drugs lopinavir, chloroquine, and remdesivir [73]. Dihydro-resveratrol (28), a metabolite of trans-resveratrol, isolated from Cannabis has antiviral activity [74]. ...
Viral diseases are extremely widespread infections caused by viruses. Amongst numerous other illnesses, viral infections have challenged human existence severely. Over the history of mankind, new viruses have emerged and presented us with new tests. The range of viral infections varies from familiar infectious diseases such as the common cold, flu, and warts to severe ailments such as AIDS, Ebola, and COVID-19. The world has been racing to find an effective cure for the newly evolving viruses. Toxic effects, non-selectivity, drug resistance, and high price are the most common complications of conventional treatment procedures. Nature is a marvelous source of phytoconstituents with incredible varieties of biological activities. By tradition, medicinal plants have been utilized for the treatment of countless infectious diseases worldwide, some of which contain a broad spectrum of activities. Modern drug discovery and development techniques offer highly efficient separation techniques, inauguration of vector-based schemes where the original infectious virus is cloned to the non-infectious one for antiviral screening targets. The objective of the review was to gather available data on 20 both cultivated and native plants of Asia giving antiviral activities and provide comprehensive information on the phytochemical analysis of the plants and potential antiviral compounds isolated from these plants.
... In this case, CBD inhibits SARS-CoV-2 replication in the early stages of the disease. This relationship is therefore indicated by Nguyen et al. as a very effective potential measure to prevent infection in the early stages of infection; however, further testing and clinical trials are needed to clearly confirm the effects of cannabidiol on this virus [97,98]. ...
This review article provides basic information about cannabis, its structure, and its impact on human development at the turn of the century. It also contains a brief description of the cultivation and application of these plants in the basic branches of the economy. This overview is also a comprehensive collection of information on the chemical composition of individual cannabis derivatives. It contains the characteristics of the chemical composition as well as the physicochemical and mechanical properties of hemp fibers, oil, extracts and wax, which is unique compared to other review articles. As one of the few articles, it approaches the topic in a holistic and evolutionary way, moving through the plant’s life cycle. Its important element is examples of the use of hemp derivatives in polymer composites based on thermoplastics, elastomers and duroplasts and the influence of these additives on their properties, which cannot be found in other review articles on this subject. It indicates possible directions for further technological development, with particular emphasis on the pro-ecological aspects of these plants. It indicates the gaps and possible research directions in basic knowledge on the use of hemp in elastomers.
... In in vivo cell culture models, CBD and ∆9-THC showed antiviral activity through the inhibition of SARS-CoV-2 translation. However, it should be mentioned that at high doses, these compounds are cytotoxic to host cells, which, in addition to the psychoactive properties of ∆9-THC, is one of the reasons why their use in medicine is limited [165]. In the treatment of COVID-19, CB2 receptor agonists should be considered potential agents in the treatment of a cytokine storm due to their strong anti-inflammatory and immunosuppressive properties. ...
Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... Ligand structures were prepared using LigPrep tools in the Schrodinger suite and optimized for minimum energy using the density functional theory (DFT) approach, as described previously Raj et al., 2021). The main reason of molecular docking was to confirm and reveal the molecular interaction between potent cinnamaldehyde analogs and highly significant genes of interest. ...
Cinnamaldehyde has a broad range of biological activities, which include antibiofilm and anthelmintic activities. The ever-growing problem of drug resistance and limited treatment options have created an urgent demand for natural molecules with antibiofilm and anthelmintic properties. Hence, we hypothesized that molecules with a scaffold structurally similar to that of cinnamaldehyde might act as dual inhibitors against fungal biofilms and helminths. In this regard, eleven cinnamaldehyde analogs were tested to determine their effects on fungal Candida albicans biofilm and nematode Caenorhabditis elegans. α-Methyl and trans-4-methyl cinnamaldehydes efficiently inhibited C. albicans biofilm formation (>90% inhibition at 50 μg/mL) with minimum inhibitory concentrations (MICs) of ≥ 200 μg/mL and 4-bromo and 4-chloro cinnamaldehydes exhibited anthelmintic property at 20 μg/mL against C. elegans. α-Methyl and trans-4-methyl cinnamaldehydes inhibited hyphal growth and cell aggregation. Scanning electron microscopy was employed to determine the surface architecture of C. albicans biofilm and cuticle of C. elegans, and confocal laser scanning microscopy was used to determine biofilm characteristics. The perturbation in gene expression of C. albicans was investigated using qRT-PCR analysis and α-methyl and trans-4-methyl cinnamaldehydes exhibited down-regulation of ECE1, IFD6, RBT5, UCF1, and UME6 and up-regulation of CHT4 and YWP1. Additionally, molecular interaction of these two molecules with UCF1 and YWP1 were revealed by molecular docking simulation. Our observations collectively suggest α-methyl and trans-4-methyl cinnamaldehydes are potent biofilm inhibitors and that 4-bromo and 4-chloro cinnamaldehydes are anthelmintic agents. Efforts are required to determine the range of potential therapeutic applications of cinnamaldehyde analogs.
... Ligands structures were collected from the PubChem library. The crystal structure of the SARS-CoV-2 M pro protein (PDB: 6LU7) [31] and RNA-dependent RNA polymerase (RdRp), PDB: 6M71 were retrieved from the RCSB protein database (https://www.rcsb.org/) at a resolution of 2.16, 2.90Å, respectively [32]. ...
The widespread outbreak of the novel coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the main health challenge worldwide. This pandemic has attracted the attention of the research communities in various fields, prompting efforts to discover rapid drug molecules for the treatment of the life-threatening COVID-19 disease. This study is aimed at investigating 4H-chromen-4-one scaffold-containing flavonoids that combat the SARS-CoV-2 virus using computational and in vitro approaches. Virtual screening studies of the molecule’s library for 4H-chromen-4-one scaffold were performed with the recently reported coronavirus main protease (Mpro, also called 3CLpro) because it plays an essential role in the maturation and processing of the viral polyprotein. Based on the virtual screening, the top hit molecules such as isoginkgetin and afzelin molecules were selected for further estimating in vitro antiviral efficacies against SARS–CoV–2 in Vero cells. Additionally, these molecules were also docked with RNA-dependent RNA Polymerase (RdRp) to reveal the ligands-protein molecular interaction. In the in vitro study, isoginkgetin showed remarkable inhibition potency against the SARS-CoV-2 virus, with an IC50 value of 22.81 μM, compared to remdesivir, chloroquine, and lopinavir with IC50 values of 7.18, 11.63, and 11.49 μM, respectively. Furthermore, the complex stability of isoginkgetin with an active binding pocket of the SARS-CoV-2 Mpro and RdRp supports its inhibitory potency against the SARS-CoV-2. Thus, isoginkgetin is a potent leading drug candidate and needs to be used in in vivo trials for the treatment of SARS-CoV-2 infected patients.
... were reported with in vitro antiviral properties against rabies virus and it was suggested that seeds of Datura can be used against rabies virus in murine model in future studies (Roy et al. 2016). A study done on Cannabis sativa L. revealed that, cannabidiol and D 9 -tetrahydrocannabinol compounds can be used as potential drug against human coronavirus and to treat COVID-19 patients (Raj et al. 2021). Hydroalcoholic formulation of belladonna (B200), consisting of atropine and scopolamine revealed its antiviral efficiency against JEV infection. ...
The goal of the evaluation of the current review is to offer a report on toxic vegetation with healthful properties and plants that are accustomed to treat infectious agent diseases (antiviral properties). Use of plants is as old as mankind, even then poisonous plants come under the most underrated category of plants all over the world and used less often due to folklores about their adverse effects. Knowledge of poisonous plants is important as some of them are useful to treat remedies. The poisonous feature of plants is due to the production of toxic substance which includes alkaloids, amines, saponins, tannins, etc. To illustrate improved affinity and effectiveness for health endorsement, they should be explored more. Along with the medicinal impact of the plants against various diseases, they are also used to treat viral diseases. Antiviral property is the most common medicinal asset of poisonous floras and used since ancient times. Natural treatment is cheap and claimed to be safe. Long ago, the investigation into antiviral action of assorted capable plants was restricted due to the extremely communicable nature of viruses and deficiency of applicable separation procedures for the documentation of antiviral plants from other plants.
As we know that, Viruses nowadays, lead to situations of pandemics all over the world. This bibliographic analysis is therefore compendium of information on plants used for the treatment of viral sicknesses.
... Phyto-cannabinoids especially CBD have exhibited a remarkable anti-inflammatory effect through CB2 inhibitory activity and agonistic effect on the peroxisome proliferator-activated receptor g (PPARg) reviewed in (Malinowska et al., 2021). Additionally, CBD, CBN, and THC have also been shown to exhibit anti-viral effect against COVID-19 in cell-based assay with the same potency as the standard clinical references (remdesivir and lopinavir) (Raj et al., 2021). However, the complete antiviral mechanism of cannabinoids against SAR-CoV2 infection is still unknown. ...
Cannabis sativa L. has been one of the oldest medicinal plants cultivated since 10,000 years for several agricultural and industrial applications. However, the plant became controversial due to some psychoactive components that have adverse effects on human health. In this review, we analyzed the trends in cannabis research for the past two centuries. We discussed the historical transitions of cannabis from the category of an herbal medicine to an illicit drug and back to a medicinal product post-legalization. In addition, we address the new-age application of immuno-suppressive and anti-inflammatory extracts for the treatment of COVID-19 inflammation. We further address the influence of the legal aspects of cannabis cultivation for medicinal, pharmaceutical, and biotechnological research. We reviewed the up-to-date cannabis genomic resources and advanced technologies for their potential application in genomic-based cannabis improvement. Overall, this review discusses the diverse aspects of cannabis research developments ranging from traditional use as an herbal medicine to latest potential in COVID, legal practices with updated patent status, and current state of art genetic and genomic tools reshaping cannabis biotechnology in modern age agriculture and pharmaceutical industry.
... In Vero cell culture models, CBD and Δ 9 -THC have shown antiviral activity via the inhibition of SARS-CoV-2 translation. However, it should be mentioned that at high doses, these compounds are cytotoxic to host cells in addition to Δ 9 -THC's psychoactive properties and their use in medicine is limited (Raj et al., 2021). In the treatment of COVID-19, CB 2 receptor agonists should be considered as potential agents in the treatment of cytokine storm due to their strong anti-inflammatory and immunosuppressive properties. ...
The global incidence of respiratory diseases and complications is increasing. Therefore, new methods of treatment, as well as prevention, need to be investigated. A group of compounds that should be considered for use in respiratory diseases is cannabinoids. There are three groups of cannabinoids – plant-derived phytocannabinoids, synthetic cannabinoids, and endogenous endocannabinoids including the enzymes responsible for their synthesis and degradation. All cannabinoids exert their biological effects through either type 1 cannabinoid receptors (CB1) and/or type 2 cannabinoid receptors (CB2). In numerous studies (in vitro and in vivo), cannabinoids and inhibitors of endocannabinoid degradation have shown beneficial anti-inflammatory, antioxidant, anti-cancer, and anti-fibrotic properties. Although in the respiratory system, most of the studies have focused on the positive properties of cannabinoids and inhibitors of endocannabinoid degradation. There are few research reports discussing the negative impact of these compounds.
This review summarizes the properties and mechanisms of action of cannabinoids and inhibitors of endocannabinoid degradation in various models of respiratory diseases. A short description of the effects selected cannabinoids have on the human respiratory system and their possible use in the fight against COVID-19 is also presented. Additionally, a brief summary is provided of cannabinoid receptors properties and their expression in the respiratory system and cells of the immune system.
... The coronaviruses have been recognized as a large enveloped positive-sense single-strand RNA viruses from Nidovirales (order) of the Coronaviridae family and subfamily Coronavirinae (Raj et al., 2021;Shamsi et al., 2021). This subfamily is classified into four genera including alpha-, beta-, gamma-, and deltacoronavirus (α-, β-, c-, and δ-CoV) based on evolutionary methods (Hulswit et al., 2016). ...
The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has now spread across the nations with high mortality rates and multifaceted impact on human life. The proper treatment methods to overcome this contagious disease are still limited. The main protease enzyme (Mpro, also called 3CLpro) is essential for viral replication and has been considered as one of the potent drug targets for treating COVID-19. In this study, virtual screening was performed to find out the molecular interactions between 36 natural compounds derived from sesame and the Mpro of COVID-19. Four natural metabolites, namely, sesamin, sesaminol, sesamolin, and sesamolinol have been ranked as the top interacting molecules to Mpro based on the affinity of molecular docking. Moreover, stability of these four sesame-specific natural compounds has also been evaluated using molecular dynamics (MD) simulations for 200 nanoseconds. The molecular dynamics simulations and free energy calculations revealed that these compounds have stable and favorable energies, causing strong binding with Mpro. These screened natural metabolites also meet the essential conditions for drug likeness such as absorption, distribution, metabolism, and excretion (ADME) properties as well as Lipinski’s rule of five. Our finding suggests that these screened natural compounds may be evolved as promising therapeutics against COVID-19.
... The complex stability of the docking conformations of the 5ID-microtubule complex was assessed using an explicit solvent of MD simulation YASARA dynamic software, as reported previously. 59 Briefly, an episodic simulation of the cell boundary sizes X, Y, and Z was assigned as 61.3, 82.8, and 52.1 Å, respectively, surrounding the entire complex and employed with an unambiguous water density of 0.997 g/L. The ions of Cl − and Na + were used randomly to attain the neutrality of charges during the MD run. ...
Coronavirus disease 2019 (COVID-19) is a global pandemic infecting the respiratory system through a notorious virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to viral mutations and the risk of drug resistance, it is crucial to identify new molecules having potential prophylactic or therapeutic effect against SARS-CoV-2 infection. In the present study, we aimed to identify a potential inhibitor of SARS-CoV-2 through virtual screening of a compound library of 470 quercetin derivatives by targeting the main protease-Mpro (PDB ID: 6LU7). The study was carried out with computational techniques such as molecular docking simulation studies (MDSS), molecular dynamics (MD) simulations, and molecular mechanics generalized Born surface area (MMGBSA) techniques. Among the natural derivatives, compound 382 (PubChem CID 65604) showed the best binding affinity to Mpro (−11.1 kcal/mol). Compound 382 interacted with LYS5, TYR126, GLN127, LYS137, ASP289, PHE291, ARG131, SER139, GLU288, and GLU290 of the Mpro protein. The SARS-CoV-2 Mpro-382 complex showed acceptable stability during the 100 ns MD simulations. The SARS-CoV-2 Mpro-382 complex also showed an MM-GBSA binding free energy value of-54.0 kcal/mol. The binding affinity, stability, and free energy results for 382 and Mpro were better than those of the native ligand and the standard inhibitors ledipasvir and cobicistat. The conclusion of our study was that compound 382 has the potential to inhibit SARS-Cov-2 Mpro. However, further investigations such as in-vitro assays are recommended to confirm its in-silico potency.
This review summarizes the pharmacological properties of tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinoid components of several species of herbal cannabis. The pharmacological effects of the phytocannabinoids have been extensively investigated and the importance of the cannabinoid receptors (CB1 and CB2) on immune cells has provided important information on the intracellular targets for these molecules. In addition to the phytocannabinoids, endogenous cannabinoids also exist in the form of anadramide and 2-srodolylglycerol (2-AG). These, together with their synthesizing and metabolizing enzymes, form the cannabinoid system. Since the discovery of the endocannabinoid system and the role that neuroinflammation plays in neurological and psychiatric illness, the potential therapeutic importance of this system has been of growing interest. In addition, the need to develop drugs which specifically target the CB1 and CB2 receptors has been stimulated by the pharmacological complexity of both THC and CBD. This review briefly summarizes the therapeutic potential of the naturally occurring and the synthetic cannabinoids which will need to be developed, if such drugs are to fulfill the therapeutic promise which the cannabinoids offer.
The main protease is regarded as an essential drug target for treating Coronavirus Disease 2019. In the present study, 13 marketed drugs were investigated to explore the possible binding mechanism, utilizing molecular docking, molecular dynamics simulation, and MM-PB(GB)SA binding energy calculations. Our results suggest that fusidic acid, polydatin, SEN-1269, AZD6482, and UNC-2327 have high binding affinities of more than 23 kcal mol-1. A descriptor was defined for the energetic occupancy of the subpocket, and it was found that S4 had a low occupancy of less than 10% on average. The molecular optimization of ADZ6482 via reinforcement learning algorithms was carried out to screen out three lead compounds, in which slight structural changes give more considerable binding energies and an occupancy of the S4 subpocket of up to 43%. The energetic occupancy could be a useful descriptor for evaluating the local binding affinity for drug design.
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, continues to be a global concern. Traditional Chinese medicines (TCMs) are an important element of the fight against COVID-19 in China. The combined application of TCMs and conventional medicines in the treatment of COVID-19 has achieved beneficial results, including the resolution of symptoms, prevention of disease progression, and reduced mortality. In this review, we summarize and discuss the current applications of TCMs with respect to COVID-19, as well as update the preclinical and clinical research, including chemical analysis, molecular mechanisms, quality control, drug development, and studies of clinical efficacy. The expectation is that a better understanding of the roles of TCMs against COVID-19 will improve the response to COVID-19, both in China and globally. © 2022 World Journal of Traditonal Chinese Medicine Published by Wolters Kluwer - Medknow.
Background:
COVID-19 highly caused contagious infections and massive deaths worldwide as well as unprecedentedly disrupting global economies and societies, and the urgent development of new antiviral medications are required. Medicinal herbs are promising resources for the discovery of prophylactic candidate against COVID-19. Considerable amounts of experimental efforts have been made on vaccines and direct-acting antiviral agents (DAAs), but neither of them was fast and fully developed.
Purpose:
This study examined the computational approaches that have played a significant role in drug discovery and development against COVID-19, and these computational methods and tools will be helpful for the discovery of lead compounds from phytochemicals and understanding the molecular mechanism of action of TCM in the prevention and control of the other diseases.
Methods:
A search conducting in scientific databases (PubMed, Science Direct, ResearchGate, Google Scholar, and Web of Science) found a total of 2172 articles, which were retrieved via web interface of the following websites. After applying some inclusion and exclusion criteria and full-text screening, only 292 articles were collected as eligible articles.
Results:
In this review, we highlight three main categories of computational approaches including structure-based, knowledge-mining (artificial intelligence) and network-based approaches. The most commonly used database, molecular docking tool, and MD simulation software include TCMSP, AutoDock Vina, and GROMACS, respectively. Network-based approaches were mainly provided to help readers understanding the complex mechanisms of multiple TCM ingredients, targets, diseases, and networks.
Conclusion:
Computational approaches have been broadly applied to the research of phytochemicals and TCM against COVID-19, and played a significant role in drug discovery and development in terms of the financial and time saving.
Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein-protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.
The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (M pro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)-derived natural alkaloids as potential inhibitors against M pro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation-based methods. Molecular docking and interaction profile analysis revealed strong binding on the M pro functional domain with four natural alkaloids viz. panicutine (−7.4 kcal/mol), vilmorrianone (−7.0 kcal/mol), denudatine (−6.0 kcal/mol), and condelphine (−5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the M pro. Additionally, mechanics/generalized Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski's rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-Cov-2), was identified for the first time in late 2019 in China, resulting in a global pandemic of massive impact. Despite a fast development and implementation of vaccination strategies, and the scouting of several pharmacological treatments, alternative effective treatments are still needed. In this regard, cannabinoids represent a promising approach because they have been proven to exhibit several immunomodulatory, anti-inflammatory, and antiviral properties in COVID-19 disease models and related pathological conditions. This mini-review aims at providing a practical brief overview of the potential applications of cannabinoids so far identified for the treatment and prevention of COVID-19, finally considering key aspects related to their technological and clinical implementation.
Medical cannabis has gained an exponential interest in recent years. Therapeutic targets have been broadened from specific applications over pain control, chemotherapy side effects, treatment-resistant epilepsies and multiple sclerosis, among others. Several in vitro and animal studies, along with few human controlled studies, suggest cannabinoids have a potential therapeutic role over medical conditions comporting inflammatory mechanisms. Given the tremendous world-wide impact of the COVID-19 pandemic, research efforts are converging towards the use of cannabinoids to attenuate severe or fatal forms of the disease. The present survey aims to explore possible correlations between cannabis use, either recreational or medical, over the presence of SARS-COV-2 contagion, along with the symptom’s severity. 4026 surveys were collected via electronic form. Results suggest a relation between any type of cannabis use and a lower risk of SARS-COV-2 contagion ( p= 0,004; OR=0,689, IC95% 0,534-0,889). Despite several methodological limitations, the present survey steps up the urge to expand our understanding on cannabinoids potential use on human controlled studies, that can better arm us in the fight against the current COVID-19 pandemic.
Introduction
Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally. However, no specific antivirals are available, although several are in development. Currently approved vaccines and other drug candidates could be associated with several drawbacks urges to develop alternative therapeutic approaches.
Aim
To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds.
Methods
Information was gathered from diverse bibliographic platforms such as PubMed, Google scholar, web of science, and ClinicalTrials.gov registry.
Results
The present review highlights the potential roles of crude extracts of plants as well as plant-derived small molecules in inhibiting SARS-CoV-2 infection by targeting viral or host factors essential for viral entry, polyprotein processing, replication, assembly and release. Their anti-inflammatory and antioxidant properties as well as plant-based therapies that are under development in the clinical trial phases-1 to 3 are also covered.
Conclusion
This knowledge could further help understanding SARS-CoV2 infection and anti-viral mechanisms of plant-based therapeutics.
Since early 2020, disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, causing millions of infections and deaths worldwide. Despite rapid deployment of effective vaccines, it is apparent that the global community lacks multipronged interventions to combat viral infection and disease. A major limitation is the paucity of antiviral drug options representing diverse molecular scaffolds and mechanisms of action. Here we report the antiviral activities of three distinct marine natural products─homofascaplysin A (1), (+)-aureol (2), and bromophycolide A (3)─evidenced by their ability to inhibit SARS-CoV-2 replication at concentrations that are nontoxic toward human airway epithelial cells. These compounds stand as promising candidates for further exploration toward the discovery of novel drug leads against SARS-CoV-2.
The current worldwide pandemic caused by coronavirus disease 2019 (COVID-19) had alerted the population to the risk that small microorganisms can create for humankind’s wellbeing and survival. All of us have been affected, directly or indirectly, by this situation, and scientists all over the world have been trying to find solutions to fight this virus by killing it or by stop/decrease its spread rate. Numerous kinds of microorganisms have been occasionally created panic in world history, and several solutions have been proposed to stop their spread. Among the most studied antimicrobial solutions, are metals (of different kinds and applied in different formats). In this regard, this review aims to present a recent and comprehensive demonstration of the state-of-the-art in the use of metals, as well as their mechanisms, to fight different pathogens, such as viruses, bacteria, and fungi.
Threading intercalators are a novel class of materials that carry two substituents along the diagonal positions of an aromatic ring. When bound to DNA, these substituents project out in DNA grooves. Tetranuclear complexes appear to be promising threading intercalators for developing therapeutics against cancer and viral infections that require high nucleic acid binding affinity. The objective of this work was to prepare the thiosemicarbazone scaffold ligand [4‐ClC6H4CHN=NC(S)NHPh] and tetranuclear cyclopalladated complex [Pd(4‐ClC6H4CHN=NC(S)NHPh)4] and to characterize the compounds by elemental analysis, 1D and 2D NMR, HRMS, and IR spectroscopy. The calf thymus DNA (CT‐DNA) binding properties of the compounds were investigated in vitro under simulated physiological conditions using UV–vis spectroscopy, emission spectral titration, methylene blue competitive binding, circular dichroism, DNA thermal denaturation, DNA binding, and coronavirus interactions using molecular simulation. The compounds showed cytotoxic effect against both human breast (MCF‐7) and colorectal (HCT116) cancer cells in a dose‐dependent manner. We demonstrated that the compounds are promising for DNA threading intercalation binders with large DNA binding constants on the order of 107 M−1 magnitude. This study shows the synthesis of novel tetranuclear cyclopalladated complex bearing thiosemicarbazone scaffold ligand, study of the ability of the complexes to interact with DNA via threading intercalators mechanism, the molecular docking with DNA and human coronavirus Mers and coronavirus disease 2019, and in vitro cytotoxicity using MTT assay.
The outbreak of COVID-19 disease has led to a search for effective vaccines or drugs. However, insufficient vaccine supplies to meet global demand and no effective approved prescribed drugs for COVID-19 have led some people to consider the use of alternative or complementary medicines, such as traditional herbal medicine. Medicinal plants have various therapeutic properties that depend on the active compounds they contain. Obviously, herbal medicine has had an essential role in treatment and prevention during COVID-19 outbreak, especially in Asian cultures. Hence, we reviewed the uses of herbal medicine in Asian cultures and described the prominent families and species that are sources of antiviral agents against COVID-19 on the basis of case reports, community surveys, and guidelines available in the literature databases. Antiviral efficacy as determined in laboratory testing was assessed, and several promising active compounds with their molecular targets in cell models against SARS-CoV-2 viral infection will be discussed. Our review findings revealed the highly frequent use of Lamiaceae family members, Zingiber officinale, and Glycyrrhiza spp. as medicinal sources for treatment of COVID-19. In addition, several plant bioactive compounds derived from traditional herbal medicine, including andrographolide, panduratin A, baicalein, digoxin, and digitoxin, have shown potent SARS-CoV-2 antiviral activity as compared with some repurposed FDA-approved drugs. These commonly used plants and promising compounds are recommended for further exploration of their safety and efficacy against COVID-19.
COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, posing an enormous threat to public health and safety. Traditional Chinese medicine (TCM), in combination with Western medicine (WM), has made important and lasting contributions in the battle against COVID-19. In this review, updated clinical effects and potential mechanisms of TCM, presented in newly recognized three distinct phases of the disease, are summarized and discussed. By integrating the available clinical and preclinical evidence, the efficacies and underlying mechanisms of TCM on COVID-19, including the highly recommended three Chinese patent medicines and three Chinese medicine formulas, are described in a panorama. We hope that this comprehensive review not only provides a reference for health care professionals and the public to recognize the significant contributions of TCM for COVID-19, but also serves as an evidence-based in-depth summary and analysis to facilitate understanding the true scientific value of TCM.
Abstract Within two decades, there have emerged three highly pathogenic and deadly human coronaviruses, namely SARS-CoV, MERS-CoV and SARS-CoV-2. The economic burden and health threats caused by these coronaviruses are extremely dreadful and getting more serious as the increasing number of global infections and attributed deaths of SARS-CoV-2 and MERS-CoV. Unfortunately, specific medical countermeasures for these hCoVs remain absent. Moreover, the fast spread of misinformation about the ongoing SARS-CoV-2 pandemic uniquely places the virus alongside an annoying infodemic and causes unnecessary worldwide panic. SARS-CoV-2 shares many similarities with SARS-CoV and MERS-CoV, certainly, obvious differences exist as well. Lessons learnt from SARS-CoV and MERS-CoV, timely updated information of SARS-CoV-2 and MERS-CoV, and summarized specific knowledge of these hCoVs are extremely invaluable for effectively and efficiently contain the outbreak of SARS-CoV-2 and MERS-CoV. By gaining a deeper understanding of hCoVs and the illnesses caused by them, we can bridge knowledge gaps, provide cultural weapons for fighting and controling the spread of MERS-CoV and SARS-CoV-2, and prepare effective and robust defense lines against hCoVs that may emerge or reemerge in the future. To this end, the state-of-the-art knowledge and comparing the biological features of these lethal hCoVs and the clinical characteristics of illnesses caused by them are systematically summarized in the review.
Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.
The current outbreak of the pandemic coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) demands its rapid, convenient, and large-scale diagnosis to downregulate its spread within as well as across the communities. But the reliability, reproducibility, and selectivity of majority of such diagnostic tests fail when they are tested either to a viral load at its early representation or to a viral gene mutated during its current spread. In this regard, a selective ‘naked-eye’ detection of SARS-CoV-2 is highly desirable, which can be tested without accessing any advanced instrumental techniques. We herein report the development of a colorimetric assay based on gold nanoparticles (AuNPs), those when capped with suitably designed thiol modified antisense oligonucleotides (ASOs) specific for N-gene (nucleocapsid phosphoprotein) of SARS-CoV-2, could be used for diagnosing positive COVID-19 cases within 10 minutes from the isolated RNA samples. The thiol modified ASO capped AuNPs agglomerate selectively in the presence of its target RNA sequence of SARS-CoV-2 and demonstrate a change in its surface plasmon resonance (SPR). Further, the addition of RNaseH cleaves the RNA strand from the RNA-DNA hybrid leading to a visually detectable precipitate from the solution mediated by the additional agglomeration among the AuNPs. The selectivity of the assay has been monitored in presence of MERS-CoV viral RNA with a limit of detection of 0.18 ng/µL of RNA having SARS-CoV-2 viral load. Thus, the current study reports a selective, and visual ‘naked-eye’ detection of COVID-19 causative virus, SARS-CoV-2, without the requirement of any sophisticated instrumental techniques.
The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development of targeted therapeutic interventions. The replication of the viral genome within the infected cells is a key stage of the SARS-CoV-2 life cycle. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. This review provides an update of the structural and functional data on the key actors of the replicatory machinery of SARS-CoV-2, to fill the gaps in the currently available structural data, which is mainly obtained through homology modeling. Moreover, learning from similar viruses, we collect data from the literature to reconstruct the pattern of interactions among the protein actors of the SARS-CoV-2 RNA polymerase machinery. Here, an important role is played by co-factors such as Nsp8 and Nsp10, not only as allosteric activators but also as molecular connectors that hold the entire machinery together to enhance the efficiency of RNA replication.
The SARS-CoV-2 is the causative agent of COVID-19 pandemic that is causing a global health emergency. The lack of targeted therapeutics and limited treatment options have triggered the scientific community to develop new vaccines or small molecule therapeutics against various targets of SARS-CoV-2. The main protease (Mpro) is a well characterized and attractive drug target because of its crucial role in processing of the polyproteins which are required for viral replication. In order to provide potential lead molecules against the Mpro for clinical use, we docked a set of 65 bioactive molecules of Tea plant followed by exploration of the vast conformational space of protein-ligand complexes by long term molecular dynamics (MD) simulations (1.50 µs). Top three bioactive molecules (Oolonghomobisflavan-A, Theasinensin-D, and Theaflavin-3-O-gallate) were selected by comparing their docking scores with repurposed drugs (Atazanavir, Darunavir, and Lopinavir) against SARS-CoV-2. Oolonghomobisflavan-A molecule showed a good number of hydrogen bonds with Mpro and higher MM-PBSA binding energy when compared to all three repurposed drugs molecules during the time of simulation. Further, MD simulations and MM-PBSA studies showed Oolonghomobisflavan-A as a potential bioactive molecule to act as an inhibitor for the Mpro of SARS-CoV-2.
The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19. A crystal structure of SARS-CoV-2 with inhibitor carmofur reveals the mechanism of action of this compound and opens the way to develop more potent drugs.
Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs-niclosamide and ciclesonide-were notable in some respects.
Now COVID-19 is causing a severe public health emergency and the mortality is rapidly increasing all over the world. In the current pandemic era, although there have been many efforts to diagnose a number of patients with symptoms or close contacts in the world to prevent the spread in the community, there is no definite guideline for the initial therapeutic approach for them and therefore, many patients have been dying due to a hyperinflammatory immunological reaction as “cytokine storm”. Severe patients are hospitalized and the treatment is done, though they have not been established yet. Currently, however, no treatment is provided for those who are isolated at home or shelter until they get severe symptoms, which will increase the harms to the patients. In this review, we discuss some important points dedicated to the management of patients with COVID-19 infections, which should help reducing morbidity and mortality. In this era, we suggested 7 recommendations to rescue the patients and to reduce the morbidity and mortality due to COVID-19 based on immunological point of view.
SARS-CoV-2 is a new generation of coronavirus, which was firstly determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-CoV-2 main protease (SARS-CoV-2 M pro) may facilitate searching for new therapies for SARS-COV-2 . The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-CoV-2 main protease by using covalent docking screening.
Method:
We conducted the covdock module MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing. Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1.
Results:
The covalent docking showed that saquinavir, ritonavir, remdesivir, delavirdine, cefuroxime axetil, oseltamivir and prevacid have the highest binding energies MMGBSA of -72.17, -72.02, -65.19, -57.65, -54.25, -51.8, -51.14 kCal/mol, respectively. 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease.
Conclusion:
The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy.
A wrench in the works of COVID-19
Understanding the inner workings of the virus that causes coronavirus disease 2019 (COVID-19) may help us to disrupt it. Yin et al. focused on the viral polymerase essential for replicating viral RNA. They determined a structure of the polymerase bound to RNA and to the drug remdesivir. Remdesivir mimics an RNA nucleotide building block and is covalently linked to the replicating RNA, which blocks further synthesis of RNA. The structure provides a template for designing improved therapeutics against the viral polymerase.
Science , this issue p. 1499
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these compounds inhibited Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
Targeting a key enzyme in SARS-CoV-2
Scientists across the world are working to understand severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). Zhang et al. determined the x-ray crystal structure of a key protein in the virus' life cycle: the main protease. This enzyme cuts the polyproteins translated from viral RNA to yield functional viral proteins. The authors also developed a lead compound into a potent inhibitor and obtained a structure with the inhibitor bound, work that may provide a basis for development of anticoronaviral drugs.
Science , this issue p. 409
The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China and spread around the world. Genomic analysis revealed that SARS-CoV-2 is phylogenetically related to severe acute respiratory syndrome-like (SARS-like) bat viruses, therefore bats could be the possible primary reservoir. The intermediate source of origin and transfer to humans is not known, however, the rapid human to human transfer has been confirmed widely. There is no clinically approved antiviral drug or vaccine available to be used against COVID-19. However, few broad-spectrum antiviral drugs have been evaluated against COVID-19 in clinical trials, resulted in clinical recovery. In the current review, we summarize and comparatively analyze the emergence and pathogenicity of COVID-19 infection and previous human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). We also discuss the approaches for developing effective vaccines and therapeutic combinations to cope with this viral outbreak.
Background:
A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients.
Methods:
All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.
Findings:
By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Interpretation:
The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies.
Funding:
Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
Objective:
To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP).
Materials and methods:
A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019.
Results:
Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324-15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods.
Conclusion:
Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP.
Trial registration:
NCT01983657. Registered 16 April 2013.
(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.
Purpose:
Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids.
Methods:
A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies.
Findings:
After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Δ-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely.
Conclusions:
Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition.
Aims:
Cannabidiol is a cannabis-derived medicinal product with potential application in a wide-variety of contexts, however its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of cannabidiol in a variety of medical contexts.
Methods:
Publications involving administration of cannabidiol alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.
Results:
A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. 23 studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 - 50 mg/Kg/day. Plasma concentrations were not provided in any publication. Cannabidiol was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of cannabidiol on reducing seizure frequency or severity (average 15 mg/Kg/day within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n=6-62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/Kg/day) were used in these studies.
Conclusion:
This review highlights cannabidiol has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.