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

The main protease (M^pro) 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 M^pro. Compound AD06 (IC₅₀ = 163.3 ± 43.5 nM) exhibited the most potent inhibitory potency against SARS-CoV-2 M^pro, 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.