Design and synthesis of isatin derivatives as effective SARS-CoV-2 3CL protease inhibitors

Hong-Lei Bao; Gao Tu; Qiu Yue; Pei Liu; Hui-Li Zheng; Xiao-Jun Yao

doi:10.1111/cbdd.14296

Design and synthesis of isatin derivatives as effective SARS-CoV-2 3CL protease inhibitors

Chem Biol Drug Des. 2023 Oct;102(4):857-869. doi: 10.1111/cbdd.14296. Epub 2023 Aug 10.

Authors

Hong-Lei Bao¹, Gao Tu¹, Qiu Yue¹, Pei Liu¹, Hui-Li Zheng¹, Xiao-Jun Yao¹

Affiliation

¹ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, China.

PMID: 37563791
DOI: 10.1111/cbdd.14296

Abstract

SARS-CoV-2 chymotrypsin-like cysteine protease (3CL^pro ) is one of the most widely developed drug targets for COVID-19. This study aimed to design and synthesize isatin derivatives to target SARS-CoV-2 3CL^pro in a covalent binding manner. Through the process, a potent 3CL^pro inhibitor (5g) was discovered with an IC₅₀ value of 0.43 ± 0.17 μM. To understand the binding affinity and specificity of 5g as a candidate inhibitor of SARS-CoV-2 3CL^pro , several assays were conducted, including FRET enzyme activity assays, thermodynamic-based and kinetic-based validation of inhibitor-target interactions, and cell-based FlipGFP assays. The interaction mechanism between 3CL^pro -5g was characterized by docking. Overall, these findings suggest that 5g is a new potent SARS-CoV-2 3CL^pro inhibitor for the treatment of COVID-19.

Keywords: FRET; FlipGFP; ITC; SARS-CoV-2 3CLpro.

Publication types

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

MeSH terms

Antiviral Agents / chemistry
COVID-19*
Humans
Isatin* / pharmacology
Molecular Docking Simulation
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2
Thermodynamics

Substances

Isatin
Protease Inhibitors
Antiviral Agents