Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy

• Published in: ACS combinatorial science Vol. 22; no. 6; pp. 297 - 305
• Main Authors: Goyal, Bhupesh, Goyal, Deepti
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.06.2020
• Subjects: Antiviral Agents - pharmacology; Betacoronavirus - chemistry; Betacoronavirus - drug effects; Betacoronavirus - enzymology; Betacoronavirus - genetics; Coronavirus 3C Proteases; Coronavirus Infections - drug therapy; Coronavirus Infections - virology; COVID-19; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Drug Discovery; Humans; Models, Molecular; Molecular Targeted Therapy; Mutation - drug effects; Pandemics; Peptides - pharmacology; Pneumonia, Viral - drug therapy; Pneumonia, Viral - virology; Protease Inhibitors - pharmacology; Protein Conformation - drug effects; Protein Multimerization - drug effects; Review; SARS-CoV-2; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; COVID-19; main protease (Mpro); mutation; SARS-CoV-2; broad-spectrum antiviral agents; SARS-CoV; dimerization; coronavirus; 3CLpro; homodimer
• ISSN: 2156-8952; 2156-8944; 2156-8944
• DOI: 10.1021/acscombsci.0c00058

A new coronavirus (CoV) caused a pandemic named COVID-19, which has become a global health care emergency in the present time. The virus is referred to as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) and has a genome similar (∼82%) to that of the previously known SARS-CoV (SARS coronavirus). An attractive therapeutic target for CoVs is the main protease (Mpro) or 3-chymotrypsin-like cysteine protease (3CLpro), as this enzyme plays a key role in polyprotein processing and is active in a dimeric form. Further, Mpro is highly conserved among various CoVs, and a mutation in Mpro is often lethal to the virus. Thus, drugs targeting the Mpro enzyme significantly reduce the risk of mutation-mediated drug resistance and display broad-spectrum antiviral activity. The combinatorial design of peptide-based inhibitors targeting the dimerization of SARS-CoV Mpro represents a potential therapeutic strategy. In this regard, we have compiled the literature reports highlighting the effect of mutations and N-terminal deletion of residues of SARS-CoV Mpro on its dimerization and, thus, catalytic activity. We believe that the present review will stimulate research in this less explored yet quite significant area. The effect of the COVID-19 epidemic and the possibility of future CoV outbreaks strongly emphasize the urgent need for the design and development of potent antiviral agents against CoV infections.