Flecainide for COVID-19

The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugsagainst Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substratebinding pocket. The top hits include anti-viral drugs such as Darunavir, Nelfinavirand Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.

Abstract Background For a deeper comprehension of the condition and the development of more potent therapies, it is essential to understand COVID-19 pathogenesis. Transmembrane serine protease 2 (TMPRSS2) and disintegrin and metalloproteinase 17 (ADAM17) are two of the most significant proteases in the pathogenesis of COVID-19. An intrinsic tissue protector with antiviral and anti-inflammatory effects is called alpha-1-antitrypsin (A1AT), and it inhibits the protein TMPRSS2, which is crucial for SARS-CoV-2-S protein priming and viral infection. It also prevents the activity of pro-inflammatory chemicals like neutrophil elastase, TNF-, and IL-8.Objective According to current findings, repurposing available medications will result in more effective functioning than using newly designed medications. Based on this, we used FDA-approved drugs and did a computational study to find out what role A1AT plays in SARS-CoV-2 infections and how it stops Covid-19 from spreading.Method This computational study comprises the screening of FDA approved drugs by using molecular networking studies via cytoscape version 3.9.1 to identify any drugs binding interactions with SERPINA1, a gene that provides instructions for making a protein called A1AT, which is a type of serine protease inhibitor, followed by the generation of a pharmacophore model, virtual screening, and docking studies.Result The 22 compounds that were selected from this molecular-networking model were subjected to pharmacophore modelling followed by virtual screening. Through this screening, we have selected 22 molecules based on the Lipinski rule and low RMSD value, i.e., below 0.069235 Ao. From the ZINC database, the top six molecules discovered were found to have a higher affinity for A1AT when compared to the co-crystal ligand (-12.8236). The highest scores obtained by alpha-1-antitrypsin (PDB ID: 7NPK) are − 22.0254 and − 21.676 for ZINC00896543 and ZINC05316843, respectively.Conclusion Consequently, the molecules found by using different software programmes may be employed to control and treat COVID 19. By increasing the levels of A1AT, we may thus infer that these molecules have excellent action in the reversal of COVID-19.

Background:Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members.Methods:Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing.Results:Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization.Conclusions:Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies.Funding:This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.