Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease

Author:

Giang Huynh-Nguyet-Huong1,Chou Feng-Pai23,Chen Ching-Yun2,Chou Shen-Chieh2ORCID,Huang Sheng-Cih2,Wu Tuoh2,Hue Bui-Thi-Buu4,Lin Hong-Cheu13,Wu Tung-Kung23

Affiliation:

1. Department of Material Science, National Yang Ming Chiao Tung University, 1001 Ta-Hsueh Rd., Hsinchu 30010, Taiwan

2. Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan

3. Center for Emergent Functional Matter Science, National Yang Ming Chiao Tung University, 1001 Ta-Hsueh Rd., Hsinchu 30010, Taiwan

4. Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho City 721337, Vietnam

Abstract

The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-Mpro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the treatment of coronavirus disease 2019 (COVID-19). In this study, a fragment-based strategy including potential antiviral quinazolinone moiety and glutamine- or glutamate-derived peptidomimetic backbone and positioned nitro functional groups was used to synthesize putative Mpro inhibitors. Two compounds, G1 and G4, exhibited anti-Mpro enzymatic activity in a dose-dependent manner, with the calculated IC50 values of 22.47 ± 8.93 μM and 24.04 ± 0.67 μM, respectively. The bio-layer interferometer measured real-time binding. The dissociation kinetics of G1/Mpro and G4/Mpro also showed similar equilibrium dissociation constants (KD) of 2.60 × 10−5 M and 2.55 × 10−5 M, respectively, but exhibited distinct association/dissociation curves. Molecular docking of the two compounds revealed a similar binding cavity to the well-known Mpro inhibitor GC376, supporting a structure−function relationship. These findings may open a new avenue for developing new scaffolds for Mpro inhibition and advance anti-coronavirus drug research.

Funder

Ministry of Science and Technology, Taiwan

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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