https://orcid.org/0000-0003-3517-8135
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Abstract
The emergence of fast-spreading SARS-CoV-2 mutants has sparked a new phase of COVID-19 pandemic. There is a dire necessity for antivirals targeting highly conserved genomic domains on SARS-CoV-2 that are less prone to mutation. The nsp12, also known as the RNA-dependent RNA-polymerase (RdRp), the core component of ‘SARS-CoV-2 replication-transcription complex’, is a potential well-conserved druggable antiviral target. Several FDA-approved RdRp ‘nucleotide analog inhibitors (NAIs)’ such as remdesivir, have been repurposed to treat COVID-19 infections. The NAIs target RdRp protein translation and competitively block the nucleotide insertion into the RNA chain, resulting in the inhibition of viral replication. However, the replication proofreading function of nsp14-ExoN could provide resistance to SARS-CoV-2 against many NAIs. Conversely, the ‘non-nucleoside analog inhibitors (NNAIs)’ bind to allosteric sites on viral polymerase surface, change the redox state; thereby, exert antiviral activity by altering interactions between the enzyme substrate and active core catalytic site of the RdRp. NNAIs neither require metabolic activation (unlike NAIs) nor compete with intracellular pool of nucleotide triphosphates (NTPs) for anti-RdRp activity. The NNAIs from phytonutrient origin are potential antiviral candidates compared to their synthetic counterparts. Several in-silico studies reported the antiviral spectrum of natural phytonutrient-NNAIs such as Suramin, Silibinin (flavonolignan), Theaflavin (tea polyphenol), Baicalein (5,6,7-trihydroxyflavone), Corilagin (gallotannin), Hesperidin (citrus bioflavonoid), Lycorine (pyrrolidine alkaloid), with superior redox characteristics (free binding energy, hydrogen-bonds, etc.) than antiviral drugs (i.e. remdesivir, favipiravir). These phytonutrient-NNAIs also exert anti-inflammatory, antioxidant, immunomodulatory and cardioprotective functions, with multifunctional therapeutic benefits in the clinical management of COVID-19.
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The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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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.
Ghulam Mustafa
Dr. Ghulam Mustafa, has earned Doctor of Philosophy in Biochemistry from University of Agriculture, Faisalabad, Pakistan with research work from Scripps Institution of Oceanography, University of California, San Diego, USA. Mustafa has a strong biochemistry background with extensive research and technology development experience in biochemistry, biotechnology, microbiology and bioinformatics. He has been working on drug discovery using both traditional and in silico approaches for more than 17 years. Dr. Mustafa has contributed more than 60 peer-reviewed research publications to the journals of international repute. Currently, he is working as an Assistant Professor of Biochemistry in Government College University Faisalabad, Pakistan.
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.