Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs

Abstract

Coronaviruses (CoVs) are positive-stranded RNA viruses that infect humans and animals. Infection by CoVs such as HCoV-229E, -NL63, -OC43 and -HKU1 leads to the common cold, short lasting rhinitis, cough, sore throat and fever. However, CoVs such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and the newest SARS-CoV-2 (the causative agent of COVID-19) lead to severe and deadly diseases with mortality rates ranging between~1 to 35% depending on factors such as age and pre-existing conditions. Despite continuous global health threats to humans, there are no approved vaccines or drugs targeting human CoVs, and the recent outbreak of COVID-19 emphasizes an urgent need for therapeutic interventions. Using computational and bioinformatics tools, here we present the feasibility of reported broad-spectrum RNA polymerase inhibitors as anti-SARS-CoV-2 drugs targeting its main RNA polymerase, suggesting that investigational and approved nucleoside RNA polymerase inhibitors have potential as anti-SARS-CoV-2 drugs. However, we note that it is also possible for SARS-CoV-2 to evolve and acquire drug resistance mutations against these nucleoside inhibitors.Pathogens 2020, 9, 320 2 of 16 there were 2494 laboratory-confirmed cases of MERS, including 858 associated deaths, mostly from Middle East countries [9]. However, the current outbreak of SARS-CoV-2, the causative agent of Coronavirus Disease 2019 (COVID-19) has claimed thousands of lives since the first reported case in December, 2019, in Wuhan city, China [10][11][12]. To date, there are no approved vaccines or anti-SARS-CoV/MERS-CoV drugs available. Hence, studies on the discovery of small molecule drugs against SARS-CoV, MERS-CoV and other related future pathogenic coronaviruses are of high importance [13].CoVs belong to the family Coronaviridae of the Nidovirales order. CoVs have been divided into α, β, γ and δ-coronavirus genera [14]. The β CoVs have been further divided into four lineages (A-D) [15]. Phylogenic analysis shows that both SARS-CoV and SARS-CoV-2 belong to lineage B of β CoVs [16,17], whereas MERS-CoV belongs is lineage C, and the well-studied mouse hepatitis virus (MHV) in lineage A [18][19][20]. An example of lineage D is Rousettus bat coronavirus HKU9 [21]. Coronaviruses are the largest (26.2 to 31.7 kb) positive [or (+)] sense single stranded RNA viruses. The polyadenylated and capped RNA genome [5,22] has multiple open reading frames (ORFs). The 5 -most two-third of the genome contains ORF1a and ORF1b that encode polyproteins pp1a and pp1ab (made through a −1 ribosomal frameshift during translation), which are cleaved to form the non-structural proteins (nsp) [23][24][25][26][27][28][29][30]. The structural proteins are expressed as subgenomic RNAs and individual RNAs (genomic and subgenomic) are translated to yield only the protein encoded by the 5'-most ORF [31]. These polyproteins are processed by coronavirus-encoded papain-like proteinases (PL pro ; within nsp3) [32] and nsp5 (3C...

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“…The ongoing pandemic coronavirus disease outbreak (COVID-2019), stemming from the beta coronavirus class (SARS-CoV-2) causing severe acute respiratory syndrome (SARS), has created a global health emergency in >200 countries around the globe ( Huang et al, 2020 ; Nalla et al, 2020 ). SARS-CoV-2, a novel coronavirus strain belonging to the Sarbecovirus subgenus (genus Betacoronavirus , family Coronaviridae ) had first appeared in late 2019, in Wuhan, China infecting a large number of hosts (>3.1 million people) with a mortality rate of ≥3.6% ( Neogi et al, 2020 ; Carter et al, 2020 ). Such putative etiopathogenic agents associated with the zoonotic viral transmission pathways are responsible for respiratory (viral pneumonia) and gastro-intestinal infections leading to multiple organ failure in infected people or patients having co-morbidities.…”