Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease

Abstract

SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papainlike protease (PL pro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PL pro strongly were three cell protectives and antioxidants (NADþ, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PL pro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PL pro over 50 ns MD simulations, with binding energy values of À56.6, À40.9, and À37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.

Histamine receptors and COVID-19

“…The SARS-CoV-2 is a zoonotic pathogen that belongs to the Betacoronavirus (β-CoV) genus of the Orthocoronavirinae subfamily of the Coronaviridae family [4]. Its genome is an enveloped, positive-sense, single-stranded genomic RNA (+ ssRNA; gRNA) of approximately 30 kilobases (kb) that shows 88-96% sequence identity to the bat coronaviruses bat-Cov RaTG13, bat-SLCoVZXC21 and bat-SL-CoVZC45 and 80% homology to the human SARS-CoV [1,5,6].…”

Union is strength: antiviral and anti-inflammatory drugs for COVID-19

“…Famotidine is an H2 antagonist and antiulcer agent with an optimal safety profile. In silico studies 66 , 67 revealed famotidine as a potential therapeutic agent against SARS-CoV-2 M pro 65 , 66 . Another study indicated that its effect is not the result of antiviral activity, but an anti-inflammatory action.…”

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

“…(84,86,87,88,89,90) Putative inhibitors of SARS-CoV-2 PL pro include FDA-approved drugs such as fostamatinib disodium (6) (a tyrosine kinase inhibitor used in the treatment of chronic immune thrombocytopenia) and natural products [e.g., platycodin D (7)]. (89,91) RNA-dependent RNA polymerase (RdRp, Nsp12) is an essential protein responsible for RNA synthesis during viral RNA transcription and replication cycles. (89) As described for SARS-CoV, the RNA polymerase activity of SAR-CoV-2 RdRp (804 aa) also seems to require the binding of Nsp7 and Nsp8 cofactors to enhance RdRp binding and processivity.…”