Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-substituted isatin compounds

Pei Liu; Hongbo Liu; Qi Sun; Hao Liang; Chunmei Li; Xiaobing Deng; Ying Liu; Luhua Lai

doi:10.1016/j.ejmech.2020.112702

Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-substituted isatin compounds

Eur J Med Chem. 2020 Nov 15:206:112702. doi: 10.1016/j.ejmech.2020.112702. Epub 2020 Aug 1.

Authors

Pei Liu¹, Hongbo Liu¹, Qi Sun¹, Hao Liang¹, Chunmei Li², Xiaobing Deng¹, Ying Liu³, Luhua Lai⁴

Affiliations

¹ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
² Center for Quantitative Biology, Peking University, Beijing, 100871, China.
³ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Center for Quantitative Biology, Peking University, Beijing, 100871, China. Electronic address: [email protected].
⁴ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Center for Quantitative Biology, Peking University, Beijing, 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. Electronic address: [email protected].

Abstract

SARS-CoV-2 3C-like protease is the main protease of SARS-CoV-2 and has been considered as one of the key targets for drug discovery against COVID-19. We identified several N-substituted isatin compounds as potent SARS-CoV-2 3C-like protease inhibitors. The three most potent compounds inhibit SARS-CoV-2 3C-like protease with IC₅₀'s of 45 nM, 47 nM and 53 nM, respectively. Our study indicates that N-substituted isatin compounds have the potential to be developed as broad-spectrum anti-coronavirus drugs.

Keywords: COVID-19; In vitro assay; N-substituted isatin compounds; SARS-CoV-2 3C-like protease; Structure-activity relationship.

MeSH terms

Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use*
Betacoronavirus / drug effects*
Coronavirus 3C Proteases
Cysteine Endopeptidases
Humans
Isatin / analogs & derivatives
Isatin / chemical synthesis
Isatin / therapeutic use*
Models, Molecular
Molecular Docking Simulation
Protease Inhibitors / chemical synthesis
Protease Inhibitors / pharmacology
Protease Inhibitors / therapeutic use*
SARS-CoV-2
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Antiviral Agents
Protease Inhibitors
Viral Nonstructural Proteins
Isatin
Cysteine Endopeptidases
Coronavirus 3C Proteases