https://orcid.org/0000-0003-3517-8135
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Abstract
The genomic reshuffling, mutagenicity, and high transmission rate of the SARS-CoV-2 pathogen highlights an urgent need for effective antiviral interventions for COVID-19 control. Targeting the highly conserved viral genes and/or gene-encoded viral proteins such as main proteinase (Mpro), RNA-dependent RNA polymerase (RdRp) and helicases are plausible antiviral approaches to prevent replication and propagation of the SARS-CoV-2 infection. Coronaviruses (CoVs) are prone to extensive mutagenesis; however, any genetic alteration to its highly conserved Mpro enzyme is often detrimental to the viral pathogen. Therefore, inhibitors that target the Mpro enzyme could reduce the risk of mutation-mediated drug resistance and provide effective antiviral protection. Several existing antiviral drugs and dietary bioactives are currently repurposed to treat COVID-19. Dietary bioactives from three ayurvedic medicinal herbs, 18 β-glycyrrhetinic acid (ΔG = 8.86 kcal/mol), Solanocapsine (ΔG = 8.59 kcal/mol), and Vasicoline (ΔG = 7.34 kcal/mol), showed high-affinity binding to Mpro enzyme than the native N3 inhibitor (ΔG = 5.41 kcal/mol). Flavonoids strongly inhibited SARS-CoV-2 Mpro with comparable or higher potency than the antiviral drug, remdesivir. Several tannin hydrolysates avidly bound to the receptor-binding domain and catalytic dyad (His41 and Cys145) of SARS‐CoV‐2 Mpro through H-bonding forces. Quercetin binding to Mpro altered the thermostability of the viral protein through redox-based mechanism and inhibited the viral enzymatic activity. Interaction of quercetin-derivatives with the Mpro seem to be influenced by the 7-OH group and the acetoxylation of sugar moiety on the ligand molecule. Based on pharmacokinetic and ADMET profiles, several phytonutrients could serve as a promising redox nutraceutical for COVID-19 management.
Acknowledgements
BHU administration, Center for Bioinformatics, School of Biotechnology, ISc, BHU for providing YASARA software.
Disclosure statement
The authors SAGN and ASN are affiliated with N-terminus Research Laboratory. The authors YBT, PS and RAC have no potential conflict of interest to disclose.
Funding
The author(s) reported there is no funding associated with the work featured in this article.
Additional information
Notes on contributors
Sreus A. G. Naidu
Dr. Sreus A.G. Naidu has earned Doctorate in Pharmacy and MS in Regulatory Science from the University of Southern California. Sreus has over 15 years of experience working at N-terminus Research Laboratory based in California, which specializes in the isolation, purification, and activation of bioactive molecules. He is co-inventor on multiple patents with applications in human nutrition and animal healthcare.
Yamini B. Tripathi
Professor Yamini B. Tripathi has earned Doctorate in Biochemistry from Banaras Hindu University (BHU). Dr. Tripathi joined the faculty in Department of Medicinal Chemistry, Institute of Medical Sciences, BHU in 1981 till date. He served four times as the Departmental Head and three years as the Dean in Faculty of Ayurveda at BHU. He has extensively validated several basic concepts in Ayurveda, biochemical and phytochemical standardization of Ayurvedic drugs to elucidate the mechanism(s) of action. He mentored more than 30 Ph.D and MD students and published over 185 peer-reviewed publications in the field of Medicinal Chemistry. Dr. Tripathi holds several patents on nutraceuticals and herbal drugs related to the management of metabolic syndromes.
Priya Shree
Dr. Priya Shree has join Ph.D program under the supervision of Prof. Yamini B. Tripathi, Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University (BHU). She has been awarded RGNF fellowship in 2017 and works as a Senior Research fellow (SRF) till date at BHU. Her expertise involves application of Bioinformatics tools to explore Ayurvedic drugs and validate their therapeutic effects. Her research is focused on metabolic syndromes including Diabetes and its complications. During COVID-19 pandemic, she worked on phyto-constituents of Ayurvedic medicinal plants and their role in clinical management of SARS-CoV-2 infections. She has published 12 peer-reviewed scientific papers in the field of Medicinal Chemistry.
Roger A. Clemens
Professor Roger A. Clemens is Associate Director of the Regulatory Science program and Adjunct Professor of Pharmacology and Pharmaceutical Sciences within the USC School of Pharmacy. Dr. Clemens was the Director of Analytical Research at USC for 5 years, and the Scientific Advisor for Nestlé USA for more than 21 years. He has published more than 50 original manuscripts in nutrition and food science, participated in more than 200 invited domestic and international lectures, and served as an expert panel member for the food industry, scientific organizations, trade associations and regulatory agencies in the United States and Canada.
A. Satyanarayan Naidu
Professor A Satyanarayan Naidu is the Director of N-terminus Research Laboratory in California, USA. After receiving PhD in Medical Microbiology (1985) from the Osmania University in India, Dr. Naidu served the Directorate of Public Health Services (DPHS), the Government of A.P., India and the World Health Organization (WHO) Surveillance program. He performed post-doctoral research at the Medical University of Pécs, Hungary and the Biomedical Center-Uppsala, Sweden. Dr. Naidu joined the faculty at the Lund University; Sweden (1988-1992), the University of North Carolina at Chapel Hill, USA (1993-1997). He was appointed as the Director at the Center for Antimicrobial Research, California State University-Pomona, USA (1998-2000). Dr. Naidu’s discoveries on Staphylococcal toxic shock syndrome (TSS) and E. coli hemolytic uremic syndrome (HUS) have garnered international recognition. He was principal investigator for several NIH grants, published more than 100 peer-reviewed research publications, written over 30 book chapters, and authored 4 reference volumes in the field of medical sciences. He holds 24 core patents, and his technology transfers in biomedical technology reach worldwide. Dr. Naidu is an elected fellow of the Royal Society for Medicine, the Linnean Society of London, the American College of Nutrition, and the International Society for the Study of Vulvovaginal Disease.