Faculty Opinions recommendation of Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.

Abstract

In late December 2019, a cluster of pneumonia cases caused by a novel coronavirus (CoV) was reported in Wuhan, China (1-3). Genomic sequencing showed that this pathogenic coronavirus is 96.2% identical to a bat coronavirus and shares 79.5% sequence identify to SARS-CoV (4-6). This novel coronavirus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses, and the pneumonia was designated as COVID-19 by the World Health Organization (WHO) on February 11, 2020 (7). The epidemic spread rapidly to more than 212 countries and was announced as a global health emergency by WHO (8). No clinically effective vaccines or specific antiviral drugs are currently available for the prevention and treatment of COVID-19 infections. The combination of α-interferon and the anti-HIV drugs Lopinavir/Ritonavir (Kaletra®) has been used, but the curative effect remains very limited and there can be toxic side effects (9). Remdesivir, a broad-spectrum antiviral drug developed by Gilead Sciences, Inc., is also being explored for the treatment of COVID-19, but more data are needed to prove its efficacy (10-12). Specific anti-SARS-CoV-2 drugs with efficiency and safety are urgently needed. A maximum likelihood tree based on the genomic sequence showed that the virus falls within the subgenus Sarbecovirus of the genus Betacoronavirus (6). Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs is approximately 30 k nt in length with a 5′-cap structure and 3′-poly-A tail, and contains at least 6 open reading frames (ORFs) (13, 14). The first ORF (ORF 1a/b), about two-third of genome length, directly translates two polyproteins: pp1a and pp1ab, because there is an a-1 frameshift between ORF1a and ORF1b. These polyproteins are processed by a main protease (M pro), also known as the 3C-like protease (3CL pro), and one or two papain-like proteases (PLPs), into 16 non-structural proteins (nsps). These nsps engage in the production of subgenomic RNAs that encode four main structural proteins (envelope (E), membrane (M), spike (S), and nucleocapsid (N) pro