Design, Synthesis, and Evaluation of Novel Thiazole-Based Peptidomimetic Compounds as Potent SARS-CoV-2 Main Protease Covalent Inhibitors

  • ACS Infect Dis. 2026 Jun 12;12(6):1915-1923. doi: 10.1021/acsinfecdis.6c00019.
Weile Yin  1 ,  Wai-Po Kong  1 ,  Siu-Lun Leung  1 ,  Zhiguang Liang  1 ,  Yu Wai Chen  1 ,  Kwok-Yin Wong  1
Affiliations
  • 1. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
PMID: 42160697 DOI: 10.1021/acsinfecdis.6c00019
Abstract

The main protease (Mpro) of SARS-CoV-2, essential for the replication of the virus, is a critical target for Antiviral drug development. Herein, we developed a series of thiazole-based peptidomimetic compounds to identify potent and selective inhibitors targeting Mpro. Compound AD06 (IC50 = 163.3 ± 43.5 nM) exhibited the most potent inhibitory potency against SARS-CoV-2 Mpro, which is comparable to Nirmatrelvir (IC50 = 160.2 ± 15.1 nM) and the lead compound MC12 (167.4 ± 28.6 nM). Crystallographic analysis revealed that AD06 and AD05 have favorable binding conformation with interactions at S1, S2, and S3/4 subsites. Notably, AD05 (EC50 = 3.22 ± 0.61 μM) displayed stronger Antiviral activity than AD06 (EC50 = 25.58 ± 0.71 μM), despite its weaker enzymatic inhibitory activity (IC50 = 306.5 ± 44.2 nM). Neither of them (CC50 > 100 μM) showed notable cytotoxicity in Vero E6 cells, highlighting AD05 as a promising candidate for further development against SARS-CoV-2.

Keywords
SARS-CoV-2 Mpro; covalent inhibitors; peptidomimetic inhibitors; structure−activity relationship; thiazole-based compounds.
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