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Amantadine as a drug to mitigate the effects of COVID-19
Abstract
The SARS-CoV-2 virus has spread around the world. At this time, there is no vaccine that can help people prevent the spread of coronavirus.
We are proposing amantadine as a drug that can be used to mitigate the effects of the virus.
It is demonstrated by docking models how amantadine can exert its action on Coronavirus viroporin E.
... Viroporin E structurally consists of 5 protein chains, formed by 75 amino acids, where 33.33% form an alpha-helix structure (hydrophobic region), 53.33% random-coil, and 13.33% extended chain [3,4]. The E protein is well conserved among the 3 corona virus groups and shows limited homology across the different groups [5,6]. ...
... The E protein was mainly located in the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) of the cells, where it participates in assembly, budding and intracellular trafficking, in addition to possessing ion channel activity [8,9]. Studies have shown that E is involved in critical aspects of the corona virus life cycle, which could make it a good candidate for the development of vaccines or drugs such as amantadine [1,4]. ...
... Molecular docking studies have shown that amantadine may interact with the amino acids ALA22 and PHE26 by blocking the protein channel [4] (Figure 1). A mechanism has also been proposed where the entry of SARS-Cov-2 into a cell depends on the binding of the viral spike protein (S) to the cell receptor and the cleavage of the spike protein by host cell proteases such as Cathepsin L (CTSL) and Cathepsin B (CATSB). ...
... Several medications were tested and included into treatment protocols [1], however till now there are no highly effective therapies available. In recent months, publications hypothesized the potential beneficial therapeutic effect of amantadine in COVID-19 treatment [2][3][4][5][6][7][8][9][10]. Currently, three clinical trials are ongoing to assess the effect of amantadine on COVID-19 compared to placebo [11][12][13]. ...
... SARS-CoV-2 in its genome has sequences encoding membrane proteins with ion channel activity (Protein E, Protein 3a, ORF7b and ORF10); amantadine can inhibit the activity of protein E and ORF10, reducing viral replication and virus-dependent inflammation [7]. It was hypothesized that amantadine has the ability to bind to the E-protein of the coronavirus ion channel, inhibiting the proton channel and thus preventing the release of viral genetic material into the cytoplasm [6]. In other publications, it is hypothesized that amantadine causes a change in the lysosomal microenvironment and their dysfunction, inhibiting the key reactions needed for SARS-CoV-2 infection [4]. ...
Background
After more than 2 years of the pandemic, effective treatment for COVID-19 is still under research. In recent months, publications hypothesized amantadine's potential beneficial effect on SARS-CoV-2 infection.
Objective
To compare the groups of Parkinson's Disease (PD) patients who were administered amantadine chronically and those who did not take this medication in the context of the incidence and severity of COVID-19 infection.
Methods
An observational, retrospective, multicenter cohort study was conducted among consecutive patients with idiopathic PD. The structured questionnaires were completed during the patient's follow-up visits at the Outpatient Clinic or during hospitalization. The questionnaire included the following informations: patient's age, duration of PD, Hoehn-Yahr (H–Y) stage, comorbidities, medications, COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2 with specified symptoms and their severity (home or hospital treatment). The vaccination status was verified as well.
Results
Five hundred fifty-two (n = 552) patients participated in the study - 329 men (60%). The mean H–Y stage was 2.44 (range: 1–4) and the mean duration of PD was 9.6 years (range: 1–34). One hundred four subjects (19%) had confirmed COVID-19 infection. Subjects over 50 years of age had a significantly lower incidence of COVID-19 (17% vs 38%, p = 0.0001) with difference also in mean H–Y stage (2.27 vs 2.49; p = 0.011) and disease duration (8.4 vs 9.9 years, p = 0.007). There were no differences between patients with and without co-morbidities. In the whole analyzed group 219 (40%) subjects were treated with amantadine. Comparing COVID-19 positive and negative patients, amantadine was used by 48/104 (46%) and 171/448 (38%) respectively. 22% of patients on amantadine vs. 17% of patients without amantadine developed COVID-19. These differences were not significant. There were no differences in morbidity and severity of COVID-19 between amantadine users and non-users as well.
Conclusions
COVID-19 was less common in older (>50) with longer duration and more advanced patients. Amantadine did not affect the risk of developing COVID-19 or the severity of infection.
... Aggregate in the brain can promote the production of neuroinflammation, etc, so COVID-19 may also indirectly affect brain function and become a risk factor for PD. Other studies have suggested that anti-PD drugs can treat COVID-19 to a certain extent, [72,73] which may explain the pathological link between PD and COVID-19, and the 2 share some common pathological mechanisms. Dopamine may be involved in the pathophysiology of COVID-19 by regulating ACE2 and dopamine decarboxylase (DDC) synthesis. ...
... The body functions and the ability to resist diseases are weakened, and there are some common pathological mechanisms between PD and COVID-19. [72,73] Because ACE2 receptor is highly expressed in dopaminergic neurons, its expression is significantly reduced in PD. Therefore, some studies speculated that there may be a reasonable relationship between ACE2 expression changes and DDC dysfunction in COVID-19 infected patients, suggesting that PD patients may be more vulnerable to coronavirus attack and lung epithelial infection. ...
The hypothesis is that there is 0a relationship between Parkinson's disease and coronavirus disease 2019 (COVID-19). By summarizing the pathogenesis of Parkinson's disease and COVID-19 and the impact of COVID-19 on the central nervous system, the relationship between Parkinson's disease and COVID-19 was analyzed, including whether Parkinson's disease is a predisposition factor for COVID-19 and whether COVID-19 causes the occurrence of Parkinson's disease. Discuss the impact of COVID-19 on patients with Parkinson's disease, including symptoms and life impact. To summarize the principles, goals and methods of home rehabilitation for Parkinson's disease patients during COVID-19. Through the analysis of this paper, it is believed that COVID-19 may cause Parkinson's disease. Parkinson's disease has the condition of susceptibility to COVID-19, but this conclusion is still controversial.
... There are several reports regarding the effect of amantadine against other viruses, including dengue virus (13,14), vesicular stomatitis virus (VSV) (15), chikungunya virus (16), severe acute respiratory syndrome coronavirus (SARS-CoV) (17), and SARS-CoV-2, the coronavirus that causes COVID-19 (18)(19)(20). For dengue virus replication in vitro, maximal inhibition occurs when amantadine is added immediately after the 90-min viral adsorption period (14). ...
... Amantadine inhibits chikungunya virus through inhibition of an ion channel activity of viroporin 6K (16). Amantadine inhibits SARS-CoV and SARS-CoV-2 through inhibiting channel activity of envelope protein, E (17,20). Amantadine also suppresses HAV IRES activities and HAV genotype IA, IB, IIIA, and IIIB replication (21)(22)(23)(24)(25). Rimantadine is effective in inhibiting human papillomavirus (HPV) infection (26). ...
Amantadine, a nonspecific antiviral medication, also effectively inhibits HAV replication. Autophagy is an important cellular mechanism in several virus-host cell interactions.
... However, all six patients receiving amantadine in the course of COVID-19 survived [61]. Since amantadine has antiviral properties against influenza A strains, and there are few studies that support amantadine's effects against COVID-19 [58,62,63], the authors recommend further investigation. The study concludes that there is no strong evidence that PD is an independent risk factor for a severe clinical course of COVID-19 and death [61]. ...
... The initial reports at the beginning of pandemic suggested that, due to its antiviral properties, amantadine (applied in PD treatment) might be effective against COVID-19 [58,62,63,65]. Amantadine interferes with viroporin protein channels responsible for the release of RNA viruses, such as SARS-CoV-2, from the infected cells [50]. ...
In this review we attempt to collate the existing scientific evidence regarding the possible role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pathophysiology of Parkinson’s disease (PD), as well as to investigate the impact of PD/parkinsonism on the clinical course of the viral infection itself. Since etiology of PD is not completely understood, various studies suggest different potential links between coronavirus disease 2019 (COVID-19) and PD. Suggested connections include, among others, similar prodromal symptoms, renin–angiotensin–aldosterone system involvement, or gut microbiome dysbiosis participation. Despite the initial assumptions that, as a mainly elderly population suffering from rigidity of respiratory muscles, impairment of cough reflex, and dyspnea, PD patients would be more susceptible to viral infection, and would experience a more aggressive course of COVID-19, the published scientific reports contain mutually exclusive data that require further investigation and meta-analysis.
... There are a few possible mechanisms as to how amantadine reduces symptoms caused by COVID-19 [10][11][12][13]. ...
... It is hypothesized that amantadine blocks the viroporin channel of SARS-CoV-2, thus disrupting the entry of the virus into the cell [10]. Another study based on a gene expression analysis showed that amantadine can downregulate the expression of the cathepsin L gene and lysosomal enzymes, subsequently decreasing viral replication [11]. ...
Amantadine, which is known for its antiviral activity, is presently used as therapy for Parkinson's disease. Adverse effects, such as cardiac arrhythmias, have been described in patients after ingestion of amantadine. Here, we present a patient who suffered a cardiac arrest following ingestion of a low dose of amantadine.
A 71-year-old man was admitted to the emergency department for a witnessed cardiac arrest. He had developed an upper respiratory tract infection the preceding week and was prescribed 100 mg of amantadine. Within half an hour of taking the first dose, the patient collapsed. He was found to be in asystole by emergency medical services, and advanced cardiac life support protocols were initiated, including cardiopulmonary resuscitation and intubation for airway protection. However, he sustained multiple recurrences of cardiac arrest, and despite all resuscitation efforts, the patient expired.
... Amantadine is an antiviral drug prescribed to treat influenza A. The mechanism of action of the drug is such that in the early stages when the virus enters the cells. It is not yet known whether this drug may work for COVID-19 [47,48]. However, due to its antiviral properties, we assume that it can reduce the symptoms of coronavirus. ...
... However, due to its antiviral properties, we assume that it can reduce the symptoms of coronavirus. In fact, amantadine blocks the COVID-19 viral purine channel and prevents the release of the viral nucleus into the cell cytoplasm [47]. There are also some papers that indicate amantadine can improve the effects of COVID-19 and most of them talked about antiviral of it [49][50][51]. ...
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus disease 2019 (COVID-19) is chronic, inflammatory. Although the exact mechanisms of COVID-19 have not been yet discovered some drugs are found helpful for its treatment. These drugs which are divided into some lines therapies, have demonstrated to be helpful for COVID-19 patients based on immune basic and its antiviral properties of the disease. Previous studies have been indicated that deterioration of COVID-19 condition is associated with a weaker immune system. Most of these therapies impact on the immune system and immune cells. Beside many beneficial effects of these drugs, some adverse effects (AE) have been reported in many experiments and clinical trials among patients suffering from COVID-19. In this review, we conclude some AEs of vitamin-D, zinc, remdesivir, hydroxychloroquine or chloroquine, azithromycin, dexamethasone, amantadine, aspirin reported in different papers and we continue the rest of the drugs in second part of our review article.
... Its proposed mechanism of action is that it blocks the early stages of viral replication. Moreover, it is hypothesized that amantadine prevents the release of the viral nucleus into the cell cytoplasm by blocking the viroporine channel of SARS-CoV-2 [96]. Very recently, Jiménez-Jiménez et al. studied the anti-inflammatory effects of amantadine and its therapeutic influence in treating COVID-19. ...
... They have suggested two pharmacological effects: antiviral and anti-inflammatory [97]. Furthermore, Abreu et al. have proposed that early use of amantadine could mitigate COVID-19 disease consequences [96]. Further randomized clinical trials are required to prove its usefulness in COVID-19 management. ...
Since the report of the first cases of pneumonia caused by SARS-CoV-2 in December 2019, COVID-19 has become a pandemic and is globally overwhelming healthcare systems. The symptoms of COVID-19 vary from asymptomatic infection to severe complicated pneumonia with acute respiratory distress syndrome (ARDS) and multiple organ failure leading to death. The estimated case-fatality rate among infected patients in Wuhan, the city where the first case appeared, was 1.4%, with 5.1 times increase in the death rate among those aged above 59 years than those aged 30-59 years. In the absence of a proven effective and licensed treatment, many agents that showed activity against previous coronavirus outbreaks such as SARS and MERS have been used to treat SARS-CoV-2 infection. The SARS-CoV-2 is reported to be 80% homologous with SARS-CoV, and some enzymes are almost 90% homologous. Antiviral drugs are urgently required to reduce case fatality-rate and hospitalizations to relieve the burden on healthcare systems worldwide. Randomized controlled trials are ongoing to assess the efficacy and safety of several treatment regimens.
... This strategy is based on the finding that COVID-induced inflammation can reduce serotonin in serum and brain [56]. However, the post-encephalitic brain exhibits a 5× hypersensitivity to psychotropic and neuropsychiatric drugs [33,57], suggesting that any drug being repurposed for long-COVID, including melatonin and selective serotonin reuptake inhibitors (SSRIs) [58], could be problematic [59,60]. Alternatively, LT is minimally invasive and elevates serotonin and its precursor tryptophan [61], suggesting that this may be the mechanism underlying the therapeutic effect seen in the present findings. ...
Background
In this case series, results from daily visual exposure to intense polychromatic light of 2000 to 4000 LUX is presented. Bright light treatment is a standard procedure for treating seasonal affective disorder and prodromal Parkinson’s disease with high success. With the post-encephalitic symptoms of long-COVID closely approximating those of prodromal Parkinson’s disease, we treated insomnia and sleep-related parameters in these patients, including total sleep, number of awakenings, tendency to fall back to sleep, and fatigue, to determine whether mending sleep could improve quality of life.
Case presentation
We present three female and two male Caucasian patients aged 42–70 years with long-COVID that persisted from 12 weeks to 139 weeks after contracting coronavirus disease.
Conclusion
A light presentation protocol was adapted for long-COVID that not only restored sleep in all patients, but also unexpectedly repaired the depression, anxiety, and cognitive changes (brain fog) as well. A robust pattern of recovery commencing 4–5 days after treatment and was maintained for weeks to months without relapse. These preliminary findings represent a novel, minimally invasive approach for managing the most debilitating symptoms of long-COVID, making it an ideal candidate for the drug hypersensitive, post-encephalitic brain. That a compromised circadian mechanism seen in Parkinson’s disease may also underlie post-encephalitic long-COVID implicates a compromised role of the circadian system in these disorders.
... Compounds like digitoxin, diammonium, ivermectin, rapamycin, rifaximin, amphotericin B, and glycyrrhizinate show desirable features and can be considered for COVID-19 therapies [183]. A recent study proposed amantadine as a therapeutic choice because it blocks the viroporine channel of COVID-19 and inhibits the release of the viral nucleus into the cytoplasm [184]. Besides lopinavir and ritonavirm, other protease inhibitors such as Nafamostat (anticoagulant), Phillyrin and chlorogenic acid effectively can prevent SARS-CoV-2 entry by inhibiting Spike protein-mediated fusion [185,186]. ...
A critical step in the drug design for SARS-CoV-2 is to discover its molecular targets. This study comprehensively reviewed the molecular mechanisms of SARS-CoV-2, exploring host cell tropism and interaction targets crucial for cell entry. The findings revealed that beyond ACE2 as the primary entry receptor, alternative receptors, co-receptors, and several proteases such as TMPRSS2, Furin, Cathepsin L, and ADAM play critical roles in virus entry and subsequent pathogenesis. Additionally, SARS-CoV-2 displays tropism in various human organs due to its diverse receptors. This review delves into the intricate details of receptors, host proteases, and the involvement of each organ. Polymorphisms in the ACE2 receptor and mutations in the spike or its RBD region contribute to the emergence of variants like Alpha, Beta, Gamma, Delta, and Omicron, impacting the pathogenicity of SARS-CoV-2. The challenge posed by mutations raises questions about the effectiveness of existing vaccines and drugs, necessitating consideration for updates in their formulations. In the urgency of these critical situations, repurposed drugs such as Camostat Mesylate and Nafamostat Mesylate emerge as viable pharmaceutical options. Numerous drugs are involved in inhibiting receptors and host factors crucial for SARS-CoV-2 entry, with most discussed in this review. In conclusion, this study may provide valuable insights to inform decisions in therapeutic approaches.
... Moreover, it must be considered that generally dopamine agonists are used in the initial or mild stages of the disease, therefore in patients less advanced in the natural history of PD. Also, amantadine, an anti-viral drug used to treat levodopainduced dyskinesia has been hypothesizing to disrupt the lysosomal machinery needed for SARS-CoV-2 replication or to block the viroporine channel of SARS-CoV-2 preventing the release of the viral nucleus into cells (58,59,61). Accordingly, to these hypotheses, several studies has been published indicating the potential role of amantadine in the prevention of the clinical symptoms related to COVID-19 (68,72). ...
SARS-CoV-2 infection leading to Coronavirus disease 19 (COVID-19) rapidly became a worldwide health emergency due to its elevated infecting capacity, morbidity, and mortality. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and, nowadays the relationship between SARS-CoV-2 outbreak and PD reached a great interest. Apparently independent one from the other, both diseases share some pathogenetic and clinical features. The relationship between SARS-CoV-2 infection and PD is complex and it depends on the direction of the association that is which of the two diseases comes first. Some evidence suggests that SARS-CoV-2 infection might be a possible risk factor for PD wherein the exposure to SARS-CoV-2 increase the risk for PD. This perspective comes out from the increasing cases of parkinsonism following COVID-19 and also from the anatomical structures affected in both COVID-19 and early PD such as olfactory bulb and gastrointestinal tract resulting in the same symptoms such as hyposmia and constipation. Furthermore, there are many reported cases of patients who developed hypokinetic extrapyramidal syndrome following SARS-CoV-2 infection although these would resemble a post-encephalitic conditions and there are to date relevant data to support the hypothesis that SARS-CoV-2 infection is a risk factor for the development of PD. Future large, longitudinal and population-based studies are needed to better assess whether the risk of developing PD after COVID-19 exists given the short time span from the starting of pandemic. Indeed, this brief time-window does not allow the precise estimation of the incidence and prevalence of PD after pandemic when compared with pre-pandemic era. If the association between SARS-CoV-2 infection and PD pathogenesis is actually putative, on the other hand, vulnerable PD patients may have a greater risk to develop COVID-19 being also more prone to develop a more aggressive disease course. Furthermore, PD patients with PD showed a worsening of motor and non-motor symptoms during COVID-19 outbreak due to both infection and social restriction. As well, the worries related to the risk of being infected should not be neglected. Here we summarize the current knowledge emerging about the epidemiological, pathogenetic and clinical relationship between SARS-CoV-2 infection and PD.
... Molecular docking studies of the 2155 ligands were carried out using Autodock Vina (version 1.2) program [73]. The docking procedure was validated by comparing the molecular interactions of amantadine on SARS-CoV-2 reported previously [74]. For all the docking simulations, the E protein was rigid and the ligands flexible. ...
Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM–PBSA calculations of the protein–ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.
... A clinical trial involving 200 COVID-19 patients treated with amantadine 200 mg/day for 14 days compared to placebo was evoked to evaluate the clinical efficacy of amantadine in COVID-19 (Rejdak et al., 2022). Abreu et al. hypoth-esized that amantadine could mitigate SARS-CoV-2 infection and associated inflammatory changes (Abreu et al., 2020). ...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The hallmarks are the presence of Lewy bodies composed mainly of aggregated α-synuclein and immune activation and inflammation in the brain. The neurotropism of SARS-CoV-2 with induction of cytokine storm and neuroinflammation can contribute to the development of PD. Interestingly, overexpression of α-synuclein in PD patients may limit SARS-CoV-2 neuroinvasion and degeneration of dopaminergic neurons; however, on the other hand, this virus can speed up the α-synuclein aggregation. The review aims to discuss the potential link between COVID-19 and the risk of PD, highlighting the need for further studies to authenticate the potential association. We have also overviewed the influence of SARS-CoV-2 infection on the PD course and management. In this context, we presented the prospects for controlling the COVID-19 pandemic and related PD cases that, beyond global vaccination and novel anti-SARS-CoV-2 agents, may include the development of graphene-based nanoscale platforms offering antiviral and anti-amyloid strategies against PD.
... Since amantadine has been successfully used in oxidative stress-related Parkinson's disease, its therapeutic activity may be based on preventing protein glycoxidation 25,26 . Recently, the potential use of amantadine has been postulated in patients with SARS-CoV infection which occurs with redox imbalance and inflammation [27][28][29][30][31][32][33][34] . However, data on the effect of amantadine on carbonyl stress are inconclusive. ...
An important drug used in the treatment of Parkinson’s disease is amantadine. We are the first to perform a comprehensive study based on various glycation and oxidation factors, determining the impact of amantadine on protein glycoxidation. Sugars (glucose, fructose, galactose) and aldehydes (glyoxal, methylglyoxal) were used as glycation agents, and chloramine T was used as an oxidant. Glycoxidation biomarkers in albumin treated with amantadine were generally not different from the control group (glycation/oxidation factors), indicating that the drug did not affect oxidation and glycation processes. Molecular docking analysis did not reveal strong binding sites of amantadine on the bovine serum albumin structure. Although amantadine poorly scavenged hydroxyl radical and hydrogen peroxide, it had significantly lower antioxidant and antiglycation effect than all protein oxidation and glycation inhibitors. In some cases, amantadine even demonstrated glycoxidant, proglycation, and prooxidant properties. In summary, amantadine exhibited weak antioxidant properties and a lack of antiglycation activity.
... In COVID-19 patients also, the use of amantadine has been recommended, and it is suggested that it could reduce the viral load (Smieszek et al. 2020;Abreu et al. 2020;Anwar et al. 2020;Araújo et al. 2020;Grieb et al. 2021). Some clinical studies have shown the beneficial effects of amantadine in SARS-CoV-2 infection (Artusi et al. 2021;Aranda-Abreu et al. 2021); however, further clinical studies (4) Isolation of patient is required to prevent the spread SARS-CoV-2 which mostly cause the anxiety and depression in patients. ...
The outbreak of SARs-CoV-2 with emerging new variants is leading to global health crisis and has brought a major concern for patients with comorbidities. Parkinson’s disease (PD) is a motor neurodegenerative disease involving various metabolic and psychological ailments along with the common occurrence of hyposmia as observed in COVID-19 patients. In addition, the observed surplus inflammatory responses in both diseases are also alarming. Alongside, angiotensin-converting enzyme 2 (ACE2) receptor, essentially required by SARS-CoV-2 to enter the cell and dopamine decarboxylase (DDC), required for dopamine synthesis is known to co-regulate in the non-neuronal cells. Taken together, these conditions suggested the probable reciprocal pathological relation between COVID-19 and PD and also suggested that during comorbidities, the disease diagnosis and therapeutics are critical and may engender severe health complications. In this review, we discuss various events and mechanisms which may have implications for the exacerbation of PD conditions and must be taken into account during the treatment of patients.
... The antiviral activity of amantadine prevents the release of viral nucleic acid into the host cell by interfering with the viral M2 protein [105]. Similarly, researchers are claiming that amantadine may interrupt the E-channel of coronavirus and thus prevent the release of the viral nucleic acids [106,107]. A retrospective cohort study evaluated amantadine among COVID-19 patients and did not find any significant effect in the treatment [108]. ...
The recent pandemic, Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has devastated humanity and is continuing to threaten us. Due to the high transmissibility of this pathogen, researchers are still trying to cope with the treatment and prevention of this disease. Few of them were successful in finding cure for COVID-19 by including repurposed drugs in the treatment. In such pandemic situations, when it is nearly impossible to design and implement a new drug target, previously designed antiviral drugs could help against novel viruses, referred to as drug repurposing/redirecting/repositioning or re-profiling. This review describes the current landscape of the repurposing of antiviral drugs for COVID-19 and the impact of these drugs on our nervous system. In some cases, specific antiviral therapy has been notably associated with neurological toxicity, characterized by peripheral neuropathy, neurocognitive and neuropsychiatric effects within the central nervous system (CNS).
... Researchers showed that DDC levels rose in asymptomatic or mild severity Covid-19 patients, while an inverse relationship was noted between SARS-CoV-2 RNA levels and DDC expression, leading them to assume a detrimental effect of DDC inhibitors on Covid-19 course Mpekoulis et al., 2021). Amantadine, a drug with mild anti-parkinsonian properties, which is classically used to manage dyskinesias in PD, has been found to exhibit anti-viral properties, while growing evidence has shown that its use might mitigate, or even prevent, the effects of Covid-19 (Abreu, Aguilar, Covarrubias, & Durán, 2020;Cort es-Borra & Aranda-Abreu, 2021;Kamel et al., 2021). Finally, an analysis of SARS-CoV-2 and human proteins revealed the Catechol-O-methyltransferase (COMT) inhibitor entacapone as a potential antiviral therapeutic agent against SARS-CoV-2 (Gordon et al., 2020). ...
People with Parkinson's Disease (PwP) may be at higher risk for complications from the Coronavirus Disease 2019 (Covid-19) due to older age and to the multi-faceted nature of Parkinson's Disease (PD) per se, presenting with a variety of motor and non-motor symptoms. Those on advanced therapies may be particularly vulnerable. Taking the above into consideration, along with the potential multi-systemic impact of Covid-19 on affected patients and the complications of hospitalization, we are providing an evidence-based guidance to ensure a high standard of care for PwP affected by Covid-19 with varying severity of the condition. Adherence to the dopaminergic medication of PwP, without abrupt modifications in dosage and frequency, is of utmost importance, while potential interactions with newly introduced drugs should always be considered. Treating physicians should be cautious to acknowledge and timely address any potential complications, while consultation by a neurologist, preferably with special knowledge on movement disorders, is advised for patients admitted in non-neurological wards. Non-pharmacological approaches, including the patient's mobilization, falls prevention, good sleep hygiene, emotional support, and adequate nutritional and fluid intake, are essential and the role of telemedicine services should be strengthened and encouraged.
... Amantadine is FDA-approved for the treatment of influenza A and its antiviral properties led its early consideration as a treatment for Covid-19 . A number of mechanisms of action of amantadine targeting SARS-CoV-2 have been proposed to limit the toxic effects of Covid-19, including disrupting lysosomal gene expression and viral replication (Aranda Abreu, Hernández Aguilar, Herrera Covarrubias, & Rojas Durán, 2020;Smieszek, Przychodzen, & Polymeropoulos, 2020). ...
The global explosion of COVID-19 necessitated the rapid dissemination of information regarding SARS-CoV-2. Hence, COVID-19 prevalence and outcome data in Parkinson's disease patients were disseminated at a time when we only had part of the picture. In this chapter we firstly discuss the current literature on the prevalence of COVID-19 in people with PD. We then discuss outcomes from COVID-19 in people with PD, specifically risk of hospitalization and mortality. Finally, we discuss specific contributing and confounding factors which may put PD patients at higher or lower risk from COVID-19.
... These data suggested that the M2 protein may be a target for adamantane drugs, and in 1992 these assumptions were confirmed [95]. In 2020, the authors [96] put forward a hypothesis in their in silico calculations that amantadine blocks the ion channel of the SARS-CoV-2 virus. It is assumed that amantadine can interact via hydrogen bonds with the amino acid residues Phe26 and Ala22 of the protein viroporin E. ...
... We want to emphasize that a virus can only grow under the right conditions. It has been investigated how amantadine works in general, and also how it can potentially work in the case of a SARS-CoV-2 infection [1][2][3]. However, for a health care professional, the most important thing is to have a drug that changes the conditions under which a virus develops in a human cell so that it cannot spread. ...
Based on 100 documented cases treated with amantadine, we suggest that with this method of treatment, at least 90%
of severe cases in Poland (or even worldwide) can be stabilized within 48-72 hours, followed by a recovery period of
several more days.
Thanks to its wide availability and the use of this well-tested drug, it will stop the disease before it causes significant
damage. It would also significantly change the way we are fighting the pandemic right now. Having an effective and safe
drug changes everything.
... Механизм антикоронавирусного действия амантадина связывают с воздействием на несколько мишеней. Входящие в структуру амантадина аминогруппы способны связываться с Е-белком ионных каналов вирусной мембраны, ингибируя ранние стадии репликации, аналогично механизму действия в отношении вируса гриппа [7]. Кроме того, амантадин действует на лизосомальные механизмы. ...
The novel coronavirus infection pandemic prompted not only the development of vaccines, but also the study of the effectiveness of already known drugs with antiviral activity. These drugs include adamantanes. Objective: to assess possible mechanisms of antiviral action of amantadine and memantine. Patients and methods. The study included 75 patients with Parkinson's disease (PD): 49 (65.3%) women and 26 (34.7%) men. The age of the patients ranged from 37 to 88 years (mean age: 65±7 years). The duration of the disease varied from 1 to 25 years (mean 12±7 years). Among the monitored PD patients, 22 (29.3%) had a novel coronavirus infection. Of 22 patients with coronavirus infection, 8 (36.4%) patients received adamantanes (four – amantadine sulfate, three – amantadine hydrochloride, one – memantine) in the complex therapy of PD for at least 3 months. On average, the duration of adamantane administration was 8±5 months. Results and discussion. PD patients who received adamantanes were less likely to develop COVID-19 than those who did not take adamantanes (p<0.05). At the same time, there were no significant differences in gender, age, duration of the disease and concomitant pathology in the com pared groups (p>0.05). Among patients who received adamantanes, the disease proceeded more easily, the number of cases of pneumonia was 3 times less (odds ratio 3; 95% confidence interval 0.44–20.3). In this group, no lethal outcomes were recorded, however, due to the small sample of patients, the differences between the groups were not statistically significant (÷2=1.99; p>0.05). Conclusion. The results of a retrospective study showed that the use of amantadine and memantine in patients with PD may have an effect on reducing morbidity and mortality in the novel coronavirus infection. This is consistent with published clinical observations suggesting a possible protective effect of amantadine and memantine against coronavirus infection.
... Active site prediction is required for molecular docking in a suitable position. According to Abreu et al. (2020) [27], establishing the hydrogen bonds with amino acid residues of Phe 26 and Ala 22 blocks the channel. The Sitemapping application was used for the prediction and validation of the active site (Maestro 10.5). ...
Numerous deaths worldwide have been caused by the coronavirus pandemic and are currently progressing with successive mutations and a lack of appropriate and definitive treatment. One of the drug targets to control the replication of the virus and treat this disease is to block the ion channel of the virus. This will lead to its death by disturbing the internal balance of the virus. Natural compounds such as alkaloids are usually known as effective compounds due to their medicinal characteristics and easy access to their sources. To this end, more than 3,200 natural alkaloid structures interacted with pentameric ion channels. Alkaloid compounds established significant and stable interactions with the channel. More clearly and in more detail, six alkaloid compounds with the best pharmacokinetics and binding affinity of less than-10.52 kcal/mol were selected as hit and suitable compounds for virus control. The compound of psammaplysin U (NA-1) with a binding affinity of-13.52 kcal/mol and binding free energy of-82.21 kcal/mol established hydrogen interactions with the amino acid of Val 25 in the B chain of the ion channel, which placed the compound at the top of the selected compounds. The molecular dynamics simulation of the ligand-protein complex in the 100 ps trajectory showed that the principal interactions were hydrogen and halogen bonding with the amino acids of Val 25 and Thr 30 in the B chain and A chain, respectively, which could be a suitable inhibitor to combat the COVID-19.
... Further, amantadine was shown to inhibit the expression of a lysosomal gene involved in the viral entry of SARS-CoV-2 in vitro [26]. Moreover, molecular docking studies predicted the binding of amantadine and memantine to several SARS-CoV-2 targets including SARS-CoV-2 protein E [27,28], of amantadine to the receptor binding domain of SARS-CoV-2 spike protein [29], and of rimantadine to the 3CL protease [30]. Finally, it was suggested that amantadine and memantine had therapeutic effects on COVID-19 by modulation of the host-immune response [31]. ...
We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.
... Of note, a case series from Poland reported five PD patients who tested positive for SARS-CoV-2 while taking amantadine, and none of them developed clinical manifestation of infectious disease [10]. These observations are intriguing because amantadine has antiviral properties against strains of influenza A. These findings may support amantadine's hypothesized biological efficacy in COVID-19 treatment [17][18][19][20]. Therefore, PD medications, like dopamine agonists, may play a role in mitigating the risk of severe COVID-19 illness in PD, but the true effect of these medications and the underlying mechanism(s) require further exploration. ...
Background
With the explosion of COVID-19 globally, it was unclear if people with Parkinson’s disease (PD) were at increased risk for severe manifestations or negative outcomes.Objectives
To report on people with PD who had suspected or confirmed COVID-19 to understand how COVID-19 manifested in PD patients.Methods
We surveyed PD patients who reported COVID-19 to their Movement Disorders specialists at Columbia University Irving Medical Center and respondents from an online survey administered by the Parkinson’s Foundation that assessed COVID-19 symptoms, general clinical outcomes and changes in motor and non-motor PD symptoms.ResultsForty-six participants with PD and COVID-19 were enrolled. Similar to the general population, the manifestations of COVID-19 among people with PD were heterogeneous ranging from asymptomatic carriers (1/46) to death (6/46). The most commonly reported COVID-19 symptoms were fever/chills, fatigue, cough, weight loss, and muscle pain. Worsening and new onset of motor and non-motor PD symptoms during COVID-19 illness were also reported, including dyskinesia, rigidity, balance disturbances, anxiety, depression, and insomnia.Conclusion
We did not find sufficient evidence that PD is an independent risk factor for severe COVID-19 and death. Larger studies with controls are required to understand this further. Longitudinal follow-up of these participants will allow for observation of possible long-term effects of COVID-19 in PD patients.
... Tipton and Wszolek [30] pointed at the antagonism of the drug at the NMDA receptors as potentially beneficial in COVID-19 and suggested that Parkinson's disease patients taking amantadine could be subject of a retrospective analysis to find out whether the drug could alleviate severe symptoms of this disease. On the basis of in silico molecular docking analysis Abreu et al. [31] hypothesised that amantadine may block the viroporin channel of COVID-19. Smieszek et al. [32] have found that in the in vitro screening assay amantadine inhibits the expression of cathepsins L and B, lysosomal proteases involved in the activation of SARS-CoV-2 S protein during virus entry into target cells. ...
Background
Whereas the World faces an unprecedented pandemic caused by the SARS-CoV-2 virus, repositioning existing drugs to treat COVID-19 disease is urgently awaited, provided that high-quality scientific evidence supporting safety and efficacy in this new indication is gathered. Efforts concerning drug repositioning to COVID-19 were mostly focused on antiviral drugs or drugs targeting the late phase of the disease.
Methods
Based on published research, the pharmacological activities of fluvoxamine and amantadine, two well-known drugs widely used in clinical practice for psychiatric and neurological diseases, respectively, have been reviewed, focusing on their potential therapeutic importance in the treatment of COVID-19.
Result
Several preclinical and clinical reports were identified suggesting that these two drugs might exert protective effects in the early phases of COVID-19.
Conclusion
Preclinical and early clinical evidence are presented indicating that these drugs hold promise to prevent COVID-19 progression when administered early during infection.
... It is a prophylactic agent targeting M2 (AM2) viroprotein channel of influenza A virus [4]. Recently, it is hypothesized that amantadine may prevent the release of the viral nucleus into the cell cytoplasm blocking the viroporine channel of COVID-19 [5]. A high throughput drug screen gene expression analysis study proposed that amantadine disrupts the lysosomal gene expression [6]. ...
Coronavirus Disease 2019 (COVID-19) infection, the pandemics, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has no known effective radical pharmacotherapy and just supportive approach at present. Amantadine is a drug used in Parkinson’s disease and other parkinsonisms; and is known to increase indirectly dopamine by antagonistic effects at the N-methyl-Daspartate (NMDA) receptor by increasing the release and blocking the reuptake of dopamine. Initially, amantadine was approved as an antiviral drug. We hypothesize that if amantadine is considered its antiviral, immunological and neurostimulant effects might be useful in the supportive treatment of SARSCoV-2 cases, especially those who developed acute respiratory failure with decreased vigilance and are being monitored in the intensive care unit. Further phase III clinical trials are needed.
... It is a prophylactic agent targeting M2 (AM2) viroprotein channel of influenza A virus [4]. Recently, it is hypothesized that amantadine may prevent the release of the viral nucleus into the cell cytoplasm blocking the viroporine channel of COVID-19 [5]. A high throughput drug screen gene expression analysis study proposed that amantadine disrupts the lysosomal gene expression [6]. ...
... In the search for a drug therapy, observations have been made that nursing-home patients with neurological diseases such as multiple sclerosis, Parkinsonism, and cognitive impairment have milder COVID-19 than comparison groups, as reported by Rejdak et al. [4]. This has stimulated discussion about the need for further research, because no randomized controlled trials have been published on this topic to date [5]. ...
Introduction
Amantadine is a well-known medication with indications in neurology and infectious diseases. It is currently FDA approved for Parkinson disease, drug induced extrapyramidal symptoms, and influenza.
Material and methods
The article is author's original research hypothesis.
Results
As more people are going to be vaccinated and more similar vaccines are going to be introduced, we should take into consideration a potential of amantadine to interfere with LNP-mRNA COVID-19 vaccine delivery into the target cells.
Conclusions
A more cautious approach to the patients taking amantadine as far as vaccination utilizing LNP-mRNA platform should be considered.
... Three independent mechanisms of action have been proposed to explain the anti-SARS-CoV-2 actions of adamantanes in general and of amantadine and memantine, in particular. These mechanisms, simply stated, are: i] Blockage of the viroporin channel of the E protein of SARS-CoV-2 preventing the release of the viral nucleus into the host cell cytoplasm [15]. ...
... недавние сообщения предполагают их возможное противовирусное действие против SARS-CoV-2. Так, Abreu et al. [72] предположили возможное противовирусное действие амантадина путем блокирования канала 5-α-спирали («канал виропорина») в гидрофобной области внутримембранной области COVID-19. Smieszek et al. [73] показали, что амантадин может подавлять экспрессию катепсина L (CTSL) и других лизосомальных ферментов, и эти два механизма были предложены как потенциально полезные для снижения способности SARS-CoV-2 проникать в клетки и уменьшать репликацию вируса. ...
SARS-CoV-2 can not only cause respiratory symptoms, but also lead to neurological complications. Research has shown that more than 30% of SARS-CoV-2 patients present neurologic symptoms during COVID-19 (A. Pezzini and A. Padovani, Nat Rev Neurol 16:636-644, 2020, https://doi.org/10.1038/s41582-020-0398-3). Increasing evidence suggests that SARS-CoV-2 can invade both the central nervous system (CNS) (M.S. Xydakis, M.W. Albers, E.H. Holbrook, et al. Lancet Neurol 20: 753-761, 2021, https://doi.org/10.1016/S1474-4422(21)00182-4) and the peripheral nervous system (PNS) (M.N. Soares, M. Eggelbusch, E. Naddaf, et al. J Cachexia Sarcopenia Muscle 13:11-22, 2022, https://doi.org/10.1002/jcsm.12896), resulting in a variety of neurological disorders. This review summarized the CNS complications caused by SARS-CoV-2 infection, including brain diseases, neurodegenerative diseases, delirium, anosmia, and smell or taste impairment. Additionally, some PNS disorders such as rheumatic diseases, skeletal muscle damage and inflammation, myasthenia gravis, Guillain-Barré syndrome, ICU-acquired weakness and post-acute sequelae of COVID-19 were described. Furthermore, the mechanisms underlying SARS-CoV-2-induced neurological disorders were also discussed, including entering the brain through retrograde neuronal or hematogenous routes, disrupting the normal function of the CNS through cytokine storms, inducing brain ischemia or hypoxia, thus leading to neurological complications. Moreover, an overview of long-COVID-19 symptoms is provided, along with some recommendations for care and therapeutic approaches of COVID-19 patients experiencing neurological complications.
The discussion has revolved around the derivatives of amino acids and peptides containing carbocycles and their potential antiviral activity in vitro against influenza A, hepatitis C viruses, and coronavirus. Studies conducted on cell cultures reveal that aminoadamantane amino acid derivatives exhibit the capacity to hinder the replication of viruses containing viroporins. Furthermore, certain compounds demonstrate potent virucidal activity with respect to influenza A/H5N1 and hepatitis C virus particles. A conceptual framework for viroporin inhibitors has been introduced, incorporating carbocyclic motifs as membranotropic carriers in the structure, alongside a functional segment comprised of amino acids and peptides. These components correspond to the interaction with the inner surface of the channel's pore or another target protein.
Background:
We investigated the association between chronic pediatric neurological conditions and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Methods:
This matched retrospective case-control study includes patients (n = 71,656) with chronic complex neurological disorders under 18 years of age, with laboratory-confirmed diagnosis of COVID-19 or a diagnostic code indicating infection or exposure to SARS-CoV-2, from 103 health systems in the United States. The primary outcome was the severity of coronavirus disease 2019 (COVID-19), which was classified as severe (invasive oxygen therapy or death), moderate (noninvasive oxygen therapy), or mild/asymptomatic (no oxygen therapy). A cumulative link mixed effects model was used for this study.
Results:
In this study, a cumulative link mixed effects model (random intercepts for health systems and patients) showed that the following classes of chronic neurological disorders were associated with higher odds of severe COVID-19: muscular dystrophies and myopathies (OR = 3.22; 95% confidence interval [CI]: 2.73 to 3.84), chronic central nervous system disorders (OR = 2.82; 95% CI: 2.67 to 2.97), cerebral palsy (OR = 1.97; 95% CI: 1.85 to 2.10), congenital neurological disorders (OR = 1.86; 95% CI: 1.75 to 1.96), epilepsy (OR = 1.35; 95% CI: 1.26 to 1.44), and intellectual developmental disorders (OR = 1.09; 95% CI: 1.003 to 1.19). Movement disorders were associated with lower odds of severe COVID-19 (OR = 0.90; 95% CI: 0.81 to 0.99).
Conclusions:
Pediatric patients with chronic neurological disorders are at higher odds of severe COVID-19. Movement disorders were associated with lower odds of severe COVID-19.
Objectives:
The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if preemptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14.
Methods:
Between 9th June 2021 and 27th January 2022, this randomized, double-blinded, placebo-controlled, single-center clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomized 1:1 to either amantadine 100 mg or placebo twice daily for five days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (i) age ≥ 40 years, age ≥ 18 years (ii) and at least one comorbidity, or - (iii) and BMI ≥ 30. The study protocol was published at www.
Clinicaltrials:
gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22).
Results:
With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm respectively. No participants in either group were admitted to hospital or died. The Odds Ratio of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (Confidence Interval 1.0-3.3, (p=0.051)). At day 7, one participant was hospitalized in each group; throughout the study this increased to five and three participants for amantadine versus placebo treatment (P=0.72). Similarly, at day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p=0.84).
Conclusions:
We found no effect of amantadine on disease progression of SARS-CoV-2 infection.
Any kind of blow, injury, shock, damage and accident inflicted on the body is considered trauma in medical science, provided that it is inflicted on the body from the outside and the internal factor is not the cause of the injury. In other words, trauma. It is any injury caused by the increase of energy input to the body. This energy may be impact, mechanical, thermal (burn), chemical or other types. Spine fracture is one of the severe injuries that can happen. In such a situation, the vertebra of the spine, which is rectangular in shape, will be compressed. This case is caused by severe traumas such as an accident or falling from a great height, but it can also be caused by osteoporosis and weakening of the bones in old age. In fact, a person who has suffered a number of blows and accidents is called multiple trauma. For example, a person who suffers a fracture, bleeding, vascular damage, amputation, etc. in an accident is a multiple trauma patient. Patients who suffer from multiples need specialized first aid and measures. According to the law, first treatment is very vital in multiple cases, depending on the place of creation, the method of providing aid is different. The way of moving the patient, the injured area, closing and transferring it, preventing possible bleedings, etc. are among the effective and decisive factors in this stage. Timely treatments prevent more and more severe injuries to the patient. Nursing in trauma is very important and effective. First, the injured person should be examined and evaluated thoroughly to determine the exact location of the trauma. Then, according to the type and level of injury, first aid should be given in trauma emergency rooms. But when it comes to mental trauma nursing, it is not only the person's body that is important. The patient should be treated appropriately. A trauma nurse should be more or less familiar with the science of psychology, the details of emotional relationships, and have great patience, because the person standing in front of him may have lost the dearest person in his life.
Introduction:
Currently, low molecular-weight compounds are being developed as potential inhibitors of CoVs replication, targeting various stages of the replication cycle, such as major protease inhibitors and nucleoside analogs. Viroporins can be alternative protein targets. The aim of this study is to identify antiviral properties of histidine derivatives with cage substituents in relation to pandemic strain SARS-CoV-2 in vitro.
Materials and methods:
Combination of histidine with aminoadamantane and boron cluster anion [B10H10]2 (compounds IIV) was carried out by classical peptide synthesis. Compound were identified by modern physicochemical methods. Antiviral properties were studied in vitro on a monolayer of Vero E6 cells infected with SARS-CoV-2 (alpha strain) with simultaneous administration of compounds and virus.
Results:
Derivatives of amino acid histidine with carbocycles and boron cluster were synthesized and their antiviral activity against SARS-CoV-2 was studied in vitro. Histidine derivatives with carbocycles and [B10H10]2 have the ability to suppress virus replication. The solubility of substances in aqueous media can be increased due to formation of hydrochloride or sodium salt.
Discussion:
2HCl*H-His-Rim (I) showed some effect of suppressing replication of SARS-CoV-2 at a viral load of 100 doses and concentration 31.2 g/ml. This is explained by the weakly basic properties of compound I.
Conclusion:
The presented synthetic compounds showed moderate antiviral activity against SARS-CoV-2. The obtained compounds can be used as model structures for creating new direct-acting drugs against modern strains of coronaviruses.
Drug repurposing is a strategy of identifying new potential uses for already existing drugs. Many researchers adopted this method to identify treatment or prevention during the COVID-19 pandemic. However, despite the considerable number of repurposed drugs that were evaluated, only some of them were labeled for new indications. In this article, we present the case of amantadine, a drug commonly used in neurology that attracted new attention during the COVID-19 outbreak. This example illustrates some of the ethical challenges associated with the launch of clinical trials to evaluate already approved drugs. In our discussion, we follow the ethics framework for prioritization of COVID-19 clinical trials proposed by Michelle N Meyer and colleagues (2021). We focus on four criteria: social value, scientific validity, feasibility, and consolidation/collaboration. We claim that launching amantadine trials was ethically justified. Although the scientific value was anticipated to be low, unusually, the social value was expected to be high. This was because of significant social interest in the drug. In our view, this strongly supports the need for evidence to justify why the drug should not be prescribed or privately accessed by interested parties. Otherwise, a lack of evidence-based argument could enhance its uncontrolled use. With this paper, we join the discussion on the lessons learned from the pandemic. Our findings will help to improve future efforts to decide on the launch of clinical trials on approved drugs when dealing with the widespread off-label use of the drug.
The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both, drugs, and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.
In fighting the COVID-19 pandemic, the main challenges include the lack of prior research and the urgency to find effective solutions. It is essential to accurately and rapidly summarize the relevant research work and explore potential solutions for diagnosis, treatment and prevention of COVID-19. It is a daunting task to summarize the numerous existing research works and to assess their effectiveness. This paper explores the discovery of new COVID-19 research approaches based on dynamic link prediction, which analyze the dynamic topological network of keywords to predict possible connections of research concepts. A dynamic link prediction method based on multi-granularity feature fusion is proposed. Firstly, a multi-granularity temporal feature fusion method is adopted to extract the temporal evolution of different order subgraphs. Secondly, a hierarchical feature weighting method is proposed to emphasize actively evolving nodes. Thirdly, a semantic repetition sampling mechanism is designed to avoid the negative effect of semantically equivalent medical entities on the real structure of the graph, and to capture the real topological structure features. Experiments are performed on the COVID-19 Open Research Dataset to assess the performance of the model. The results show that the proposed model performs significantly better than existing state-of-the-art models, thereby confirming the effectiveness of the proposed method for the discovery of new COVID-19 research approaches.
Introdução: Desde o início do ano de 2020, a coronavírus-19 (COVID-19), uma doença de cunho viral, com sintomas predominantemente respiratórios, vem assolando a humanidade. Mesmo em 2022, ainda pode-se afirmar que há deficiência de fármacos para prevenir e tratar tal mal. Objetivo: Analisar os efeitos profiláticos e terapêuticos do uso da amantadina na COVID-19. Método: Foi realizada uma revisão sistemática do tipo integrativa. Para tanto, foram utilizadas as bases de dados Medical Publication, Biblioteca Virtual em Saúde, Business Source Complete, Medical Literature Analysis and Retrievel System Online e ScienceDirect, a partir dos Descritores em Ciências de Saúde “Amantadina” e “COVID-19”. A partir dos critérios de elegibilidade, a amostra final contemplou um total de 18 artigos. Resultados: Após a análise dos estudos selecionados, foi visto que a maioria dos artigos comprovaram a eficácia da profilaxia da amantadina, mostrando que ela age nos canais do vírus, impedindo tanto a sua progressão quanto o aparecimento da infecção no organismo. Conclusão: Conclui-se que a profilaxia e terapia com uso da amantadina na COVID-19 é uma alternativa diante de tal cenário epidemiológico, porém necessitando de mais estudo.
Palavras-chave: SARS-CoV-2; Prevenção de Doenças; Tratamento Farmacológico.
Over the past few years, antiviral drugs against influenza are considered emerging contaminants since they cause environmental toxicity even at low concentrations. They have been found in environmental matrices all around the world, showing that conventional treatment methods fail to remove them from water and wastewater. In addition, the metabolites and transformation products of these drugs can be more persistent than original in the environment. Several techniques to degrade/remove antiviral drugs against influenza have been investigated to prevent this contamination. In this study, the characteristics of antiviral drugs against influenza, their measurement by analytical methods, and their removal in both water and wastewater treatment plants (WWTPs) were presented. Different treatment methods, such as traditional procedures (biological processes, filtration, coagulation, flocculation, and sedimentation), advanced oxidation processes (AOPs), adsorption and combined methods, were assessed. Ecotoxicological effects of both the antiviral drug and its metabolites as well as the transformation products formed as a result of treatment were evaluated. In addition, future perspectives for improving the removal of antiviral drugs against influenza, their metabolites and transformation products were further discussed. The research indicated that the main tested techniques in this study were ozonation, photolysis and photocatalysis. Combined methods, particularly those that use renewable energy and waste materials, appear to be the optimum approach for the treatment of effluents containing antiviral drugs against influenza. In light of high concentrations or probable antiviral resistance, this comprehensive assessment suggests that antiviral drug monitoring is required, and some of those substances may cause toxicological effects.
The article provides an overview of the data on the impact of Parkinson's disease on the risk of infection and the course of COVID-19, and also assesses the possible pathogenetic relationship between the SARS-CoV-2 virus, COVID-19 and PD. By penetrating the central nervous system, SARS-CoV-2 can cause not only neurological symptoms, but also exacerbate the course of an existing neurological disease. The impact of Parkinson's disease on the risk of infection and the course of COVID-19 is controversial. However, a number of authors support the opinion that PD is an anti-risk factor for the development of COVID-19, which is associated both with the pathogenesis of the disease and with the used antiparkinsonian drugs, in particular amantadines. There are no clear data indicating higher risk of infection and higher severity of COVID-19 in patients with PD. On the contrary, experimental and clinical data suggest a possible modifying role of α-synuclein and antiparkinsonian drugs.
Target-based design and repositioning are mainstream strategies of drug discovery. Numerous drug design and repositioning projects have been launched to fight the ongoing COVID-19 pandemic. The resulting drug candidates have often failed due to the misprediction of their target-bound structures. The determination of water positions of such structures is particularly challenging due to the large number of possible drugs and the diversity of their hydration patterns. To answer this challenge and help correct predictions, we introduce a new protocol HydroDock, which can build hydrated drug–target complexes from scratch. HydroDock requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, we built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head. As HydroDock supplied otherwise undetermined structural details, it can be recommended to improve the reliability of future design and repositioning of antiviral drug candidates and many other ligands with an influence of water structure on their mechanism of action.
Mental health disorders are closely related to COVID-19 at the biological, psychological, and social levels, and they are receiving more and more attention now. Mental and behavioral disorders may be the manifestations or complications of acute COVID-19, such as acute psychotic disorders, more often in the form of hyperactive delirium, cognitive impairment, anxiety disorders, sleep disorders, depression, and suicide attempts. The post-Covid period is also represented by a wide range of mental disorders, when cognitive impairment, anxiety, depression, and PTSD come to the fore. The problem of early diagnosis and complex therapy of mental disorders associated with COVID-19 at all stages of the disease can be successfully solved using a holistic psychosomatic approach. Medical and psychological support and counseling psychiatric care are provided mainly in the mode of telemedicine. When prescribing psychotropic drugs, the doctor should take into account the risk of drug interactions: lopinavir/ritonavir, chloroquine/hydroxychloroquine, and antibiotics often give potentially dangerous combinations with psychotropic drugs in the treatment of acute COVID-19. At the same time, remdesivir, favipiravir, tocilizumab, baricitinib, and anakinra can be used concomitantly with psychotropic drugs without significant risk of drug interaction (except for the hematological risk with clozapine and baricitinib). The article presents international and national recommendations for the selection of the most effective therapy for mental disorders (antipsychotics, antidepressants, thymostabilizers, and anxiolytics) during acute COVID-19, indicating the doses and mode of administration. The recommendations for the management of the consequences of COVID-19 from the standpoint of evidence-based medicine are also given.
Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson’s disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications.
The article presents data from recent studies on the mechanisms of action and clinical efficacy of amantadines, and also describes a possible protective effect against COVID-19.
Objective:
To evaluate the association between sleep-wake rhythm and cardiometabolic parameters.
Material and methods:
103 participants, aged 25-64 years, underwent actigraphy study with Actigraph Actilife GT3X + device (USA) for 7 days. We assessed actigraphy indicators (physical activity and sleep data), anthropometric indicators, blood pressure and laboratory parameters. Actigraphy data was processed using the nparACT package in the R program with the calculation of nonparametric indicators: intraday variability, interday stability, the average level of lowest activity for five hours (L5) and ten hours with the highest activity (M10), relative amplitude is the ratio of M10/L5.
Results:
The nonparametric analysis showed an association of the higher night activity with sleep effectiveness, wake after sleep onset, indicators of physical activity. A more stable sleep pattern is associated with more steps, less weight and waist circumference, lower levels of diastolic blood pressure, creatinine and insulin. Increased fragmentation of sleep patterns is associated with increased CRP and increased sedentary time. Participants with higher activity contrast have less waist circumference, hips and body mass index, lower levels of CRP and insulin.
Conclusions:
Rhythm and quality of sleep are important parameters associated with cardiometabolic indicators. Stable sleep patterns, higher activity during the day and lower night activity are associated with a more favorable condition of cardiovascular system.
Dear Editor,
In the midst of the new coronavirus pandemic which originated in Wuhan (China) at the end of 2019, all types of treatment, prevention and patient care strategies for those infected by SARS-CoV-2 have been proposed. People are working incessantly to obtain a drug or combination of drugs which would be capable of defeating the virus and dealing with the infection: hydroxychloroquine, remdesivir, favipravir and merimepodib, lopinavir, ritonavir, dexamethasone anti-inflammatory agents, anticoagulants, astemizole and clofazamine among others. In the very short time since SARS-CoV-2 began many types of drugs have been tried and unfortunately, many of them have been ruled out for their inefficacy against the virus. Furthermore, different vaccines are being developed, now in clinical research phases.
At a virological level, SARS-CoV-2 can cause acute, highly lethal pneumonia (COVID-19) with one of the most common symptoms being difficulty in breathing, sustained fever and fatigue; and the great majority of patients in intensive care units require mechanical ventilation. It has also been reported that SARS-CoV-2 has a neurotropical activity with neurological consequences, leading to breathing difficulties due to the invasion of the virus in the brain stem. The highest mortality rates are among the geriatric population and people with comorbidities and immunological dysfunction.
In the midst of the pandemic, amantadine has recovered particular interest, since several authors suggest the hypothesis that it may be protective against SARS-CoV-2 infection. Amantadine is an inexpensive drug, compared with others. It is an antiviral against influenza type A which inhibits the attachment of viral particles and subsequent release of nucleic acid, preventing the fusion of the viral envelope with the vacuole membrane, which interferes with the penetration of the virus through the cell membrane. It may be used for the treatment of symptoms and as prophylaxis of the flu virus. It is also used in patients with Parkinson’s disease, for the treatment of symptoms such as stiffness, shaking, hypokinesia and akinesia, since it is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist which acts on glutamatergic transmission, correcting the imbalance between glutamatergic and dopaminergic pathways. As such, it improves dopaminergic response of the central nervous system (CNS), releases stored dopamine and norepinyphrine, and prevents re-uptake.
Aranda suggested that amantadine blocks the viroporin channel of COVID-19, preventing the release of the viral nucleus to the cell cytoplasm.1 Redjak et al.2 assessed the severity of COVID-19 in patients with multiple sclerosis, Parkinson’s disease and cognitive impairment, with infection by SARS-CoV-2 confirmed by the polymerase chain reaction (PCR), all of whom received treatment with amantadine or memantine and none of whom developed clinical COVID-19 symptoms. Tipton et al.3 proposed amantadine and memantine as two potential candidates for their cost-effectiveness and low risk. Cimolai4 suggests that the laboratories should include adamantanes for assessment against COVID-19. Smieszek et al.5 put forward the hypothesis that amantadine could reduce the viral load in patients testing positive for SARS-CoV-2, since it reduces the replication and infectiousness of the virus. Araújo et al.6 considered that amantadinae could reduce the effects of COVID-19, including acute respiratory distress syndrome (ARDS), viral replication and ventilator-dependency. Wiwanitkit7 affirmed that there are many standard drugs which would be useful for the treatment of COVID-19, among which are amantadinae. Cortés-Borra8 commented on a clinical case study of a patient who was taking amantadine to mitigate the effects of Parkinson’s and did not contract the coronavirus disease, despite being in close and continuous contact with her husband, who did contract COVID-19 and died from it.
Support for father research and an exchange of knowledge are therefore needed to provide healthcare systems with useful tools in the prevention and treatment of this serious health crisis. A low risk and affordable strategy would be the re-use of inexpensive and easily available drugs such as the adamantanes. Amantadine may prevent the development of symptoms in people who are asymptomatic and reduce the number of deaths. At this current time of uncertainty when hundreds of deaths are due to infection by COVID-19, alternatives must be found to mitigate the effects of the coronavirus, in the absence of any available vaccine.
Malaria is an infectious disease caused by Plasmodium group. The mechanisms of antimalarial drugs DHA/CQ are still unclear today. The inhibitory effects (IC50) of single treatments with DHA/CQ or V-ATPase inhibitor Baf-A1 or combination treatments by DHA/CQ combined with Baf-A1 on the growth of Plasmodium falciparum strain 3D7 was investigated. Intracellular cytoplasmic pH and labile iron pool (LIP) were labeled by pH probe BCECF, AM and iron probe calcein, AM, the fluorescence of the probes was measured by FCM. The effects of low doses of DHA (0.2 nM, 0.4 nM, 0.8 nM) on gene expression of V-ATPases (vapE, vapA, vapG) located in the membrane of DV were tested by RT-qPCR. DHA combined with Baf-A1 showed a synergism effect (CI = 0.524) on the parasite growth in the concentration of IC50. Intracellular pH and irons were effected significantly by different doses of DHA/Baf-A1. Intracellular pH was decreased by CQ combined with Baf-A1 in the concentration of IC50. Intracellular LIP was increased by DHA combined with Baf-A1 in the concentration of 20 IC50. The expression of gene vapA was down-regulated by all low doses of DHA (0.2/0.4/0.8 nM) significantly (p < 0.001) and the expression of vapG/vapE were up-regulated by 0.8 nM DHA significantly (p < 0.001). Interacting with ferrous irons, affecting the DV membrane proton pumping and acidic pH or cytoplasmic irons homeostasis may be the antimalarial mechanism of DHA while CQ showed an effect on cytoplasmic pH of parasite in vitro. Lastly, this article provides us preliminary results and a new idea for antimalarial drugs combination and new potential antimalarial combination therapies.
A recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major determinant of virulence. Elimination of SARS-CoV E protein PBM by using reverse genetics caused a reduction in the deleterious exacerbation of the immune response triggered during infection with the parental virus and virus attenuation. Cellular protein syntenin was identified to bind the E protein PBM during SARS-CoV infection by using three complementary strategies, yeast two-hybrid, reciprocal coimmunoprecipitation and confocal microscopy assays. Syntenin redistributed from the nucleus to the cell cytoplasm during infection with viruses containing the E protein PBM, activating p38 MAPK and leading to the overexpression of inflammatory cytokines. Silencing of syntenin using siRNAs led to a decrease in p38 MAPK activation in SARS-CoV infected cells, further reinforcing their functional relationship. Active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM as compared with the parental virus, leading to a decreased expression of inflammatory cytokines and to virus attenuation. Interestingly, administration of a p38 MAPK inhibitor led to an increase in mice survival after infection with SARS-CoV, confirming the relevance of this pathway in SARS-CoV virulence. Therefore, the E protein PBM is a virulence domain that activates immunopathology most likely by using syntenin as a mediator of p38 MAPK induced inflammation.
Here, we describe two freely available web servers for molecular docking. The PatchDock method performs structure prediction
of protein–protein and protein–small molecule complexes. The SymmDock method predicts the structure of a homomultimer with
cyclic symmetry given the structure of the monomeric unit. The inputs to the servers are either protein PDB codes or uploaded
protein structures. The services are available at http://bioinfo3d.cs.tau.ac.il. The methods behind the servers are very efficient, allowing large-scale docking experiments.
Background
Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads.
Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.
Results
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms.
Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
Conclusion
Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here, we show that small molecules can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using X-ray crystallography have been limited due to the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resolution. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. These drug-bound complexes provide the first high-resolution structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.
Coronaviruses (CoV) cause common colds in humans, but are also responsible for the recent Severe Acute, and Middle East, respiratory syndromes (SARS and MERS, respectively). A promising approach for prevention are live attenuated vaccines (LAVs), some of which target the envelope (E) protein, which is a small membrane protein that forms ion channels. Unfortunately, detailed structural information is still limited for SARS-CoV E, and non-existent for other CoV E proteins. Herein, we report a structural model of a SARS-CoV E construct in LMPG micelles with, for the first time, unequivocal intermolecular NOEs. The model corresponding to the detergent-embedded region is consistent with previously obtained orientational restraints obtained in lipid bilayers and in vivo escape mutants. The C-terminal domain is mostly α-helical, and extramembrane intermolecular NOEs suggest interactions that may affect the TM channel conformation.
A computer program that progressively evaluates the hydrophilicity and hydrophobicity of a protein along its amino acid sequence has been devised. For this purpose, a hydropathy scale has been composed wherein the hydrophilic and hydrophobic properties of each of the 20 amino acid side-chains is taken into consideration. The scale is based on an amalgam of experimental observations derived from the literature. The program uses a moving-segment approach that continuously determines the average hydropathy within a segment of predetermined length as it advances through the sequence. The consecutive scores are plotted from the amino to the carboxy terminus. At the same time, a midpoint line is printed that corresponds to the grand average of the hydropathy of the amino acid compositions found in most of the sequenced proteins. In the case of soluble, globular proteins there is a remarkable correspondence between the interior portions of their sequence and the regions appearing on the hydrophobic side of the midpoint line, as well as the exterior portions and the regions on the hydrophilic side. The correlation was demonstrated by comparisons between the plotted values and known structures determined by crystallography. In the case of membrane-bound proteins, the portions of their sequences that are located within the lipid bilayer are also clearly delineated by large uninterrupted areas on the hydrophobic side of the midpoint line. As such, the membrane-spanning segments of these proteins can be identified by this procedure. Although the method is not unique and embodies principles that have long been appreciated, its simplicity and its graphic nature make it a very useful tool for the evaluation of protein structures.
The influenza A virus M2 integral membrane protein has ion channel activity which can be blocked by the antiviral drug amantadine. The M2 protein transmembrane domain is highly conserved in amino acid sequence for all the human, swine, equine, and avian strains of influenza A virus, and thus, known amino acid differences could lead to altered properties of the M2 ion channel. We have expressed in oocytes of Xenopus laevis the M2 protein of human influenza virus A/Udorn/72 and the avian virus A/chicken/Germany/34 (fowl plague virus, Rostock) and derivatives of the Rostock ion channel altered in the presumed pore region. The pH of activation of the M2 ion channels and amantadine block of the M2 ion channels were investigated. The channels were found to be activated by pH in a similar manner but differed in their apparent Kis for amantadine block.
The lysosomotropic nature of amantadine suggested potential as an antimalarial. Sensitivity tests to amantadine hydrochloride alone and in combination with chloroquine were carried out in 96-well microtitre plates using the tritiated hypoxanthine uptake method to measure parasite growth. Amantadine alone has antimalarial activity. Amantadine is more potent against chloroquine-resistant strains. Combinations of amantadine and chloroquine result in slight synergy in both resistant and sensitive strains.
The coronavirus responsible for the severe acute respiratory syndrome (SARS-CoV) contains a small envelope protein, E, with putative involvement in host cell apoptosis and virus morphogenesis. It has been suggested that E protein can form a membrane destabilizing transmembrane (TM) hairpin, or homooligomerize to form a regular TM alpha-helical bundle. We have shown previously that the topology of the alpha-helical putative TM domain of E protein (ETM), flanked by two lysine residues at C and N termini to improve solubility, is consistent with a regular TM alpha-helix, with orientational parameters in lipid bilayers that are consistent with a homopentameric model. Herein, we show that this peptide, reconstituted in lipid bilayers, shows sodium conductance. Channel activity is inhibited by the anti-influenza drug amantadine, which was found to bind our preparation with moderate affinity. Results obtained from single or double mutants indicate that the organization of the transmembrane pore is consistent with our previously reported pentameric alpha-helical bundle model.