Perspectives on SARS-CoV-2 Main Protease Inhibitors

Abstract

The main protease (Mpro) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 Mpro designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV Mpro inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure–activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of Mpro inhibitors for SARS-CoV-2 and future coronavirus diseases.

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

“…Since then, thousands of compounds have been suggested as SARS-CoV-2 M-pro inhibitors through computational methods such as protein-ligand docking, high-throughput screening experiments, computer-aided design and synthesis of new compounds. Several articles have reviewed the SARS-CoV-2 M-pro inhibitors discovered to date [ 25 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In this review, we collected 1765 SARS-CoV-2 M-pro inhibitors from the bibliography and other sources such as the COVID Moonshot project [ 39 , 40 ] and the ChEMBL release 29 database [ 41 ].…”

Identification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (Mpro) inhibitors

“…1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 63 , 64 .…”

A highly sensitive cell-based luciferase assay for high-throughput automated screening of SARS-CoV-2 nsp5/3CLpro inhibitors

“…Paxlovid has been authorized for use by the FDA in december 2021 and by the EMA in January 2022, which represents a major advance for pandemic management. Although the structure of the active site of nsp5 is highly conserved among coronaviruses, and its sequence shows very few variations among the >1.9 millions SARS-CoV-2 full-genome available to date ( Gao et al, 2021 ), the emergence of viruses with drug-resistant mutations cannot be excluded. The identification of other anti-SARS-CoV-2 drugs therefore remains a high priority.…”