Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814

Jian Li; Cheng Lin; Xuelan Zhou; Fanglin Zhong; Pei Zeng; Peter J McCormick; Haihai Jiang; Jin Zhang

doi:10.1016/j.jmb.2022.167706

Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814

J Mol Biol. 2022 Aug 30;434(16):167706. doi: 10.1016/j.jmb.2022.167706. Epub 2022 Jul 6.

Authors

Jian Li¹, Cheng Lin², Xuelan Zhou³, Fanglin Zhong³, Pei Zeng³, Peter J McCormick⁴, Haihai Jiang⁵, Jin Zhang⁶

Affiliations

¹ College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China.
² School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
³ Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen 518118, China; Jiangxi Jmerry Biopharmaceutical Co., Ltd, Ganzhou 341000, China.
⁴ Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
⁵ School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China. Electronic address: haihaijiang2020@ncu.edu.cn.
⁶ School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China. Electronic address: zhangxiaokong@hotmail.com.

Abstract

New variants of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) emerged and spread rapidly all over the world, which strongly supports the need for pharmacological options to complement vaccine strategies. Main protease (M^pro or 3CL^pro) is a critical enzyme in the life cycle of SARS-CoV-2 and appears to be highly conserved among different genera of coronaviruses, making it an ideal target for the development of drugs with broad-spectrum property. PF-07304814 developed by Pfizer is an intravenously administered inhibitor targeting SARS-CoV-2 M^pro. Here we showed that PF-07304814 displays broad-spectrum inhibitory activity against M^pros from multiple coronaviruses. Crystal structures of M^pros of SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-NL63 bound to the inhibitor PF-07304814 revealed a conserved ligand-binding site, providing new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures complemented by comprehensive comparison defined the key structural determinants essential for inhibition and illustrated the binding mode of action of M^pros from different coronaviruses. In view of the importance of M^pro for the medications of SARS-CoV-2 infection, insights derived from the present study should accelerate the design of pan-coronaviral main protease inhibitors that are safer and more effective.

Keywords: PF-07304814; coronavirus; inhibitor; main protease; structural basis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Coronavirus 3C Proteases* / antagonists & inhibitors
Coronavirus 3C Proteases* / chemistry
Coronavirus Protease Inhibitors* / chemistry
Coronavirus Protease Inhibitors* / pharmacology
Drug Design
Humans
Indoles* / chemistry
Indoles* / pharmacology
Leucine* / chemistry
Leucine* / pharmacology
Ligands
Protein Binding
Pyrrolidinones* / chemistry
Pyrrolidinones* / pharmacology
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology

Substances

Coronavirus Protease Inhibitors
Indoles
Ligands
Pyrrolidinones
3C-like protease, SARS coronavirus
Coronavirus 3C Proteases
Leucine
lufotrelvir