Antiviral drug resistance in SARS-CoV-2 is increasingly limiting treatment efficacy. Four recent studies have revealed two key resistance mechanisms: (1) Mutations in the main protease (Mpro)—including E166V, E166A, and S144-series variants—disrupt drug binding or active-site conformation, reducing nirmatrelvir efficacy. (2) The proofreading exoribonuclease (ExoN) removes incorporated nucleoside analogues (e.g., bemnifosbuvir, sofosbuvir), conferring resistance. Guided by structural and pharmacological insights, three effective countermeasures have been established: structure-based optimization of Mpro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies. These advances provide a solid framework for developing next-generation antivirals to combat emerging resistant SARS-CoV-2 variants.
Xianghan Bai, Bing Ye, Sheng-Hua Gao et al.· Molecules· 0 citations
The continuous evolution of SARS-CoV-2 and the emergence of drug-resistant variants underscore the urgent need for broad-spectrum antiviral agents targeting conserved viral proteins. The main protease (Mpro) represents a promising target due to its essential role in coronavirus replication. In this study, we report the discovery and optimization of a novel series of piperazine-based Mpro inhibitors using a multi-site binding strategy guided by analysis of conserved residues within the coronavirus Mpro active sites. Starting from the noncovalent lead GC-14, systematic optimization of substituents occupying the S1', S1, S2, and S4 subsites of Mpro led to the development of the noncovalent inhibitor GY-e2, which showed improved inhibitory efficacy against both SARS-CoV-2 and SARS-CoV Mpro. To further enhance its antiviral efficacy in cellular models, reactive warheads targeting C145 were incorporated into the scaffold to generate covalent inhibitors. This strategy yielded the isomeric compounds Y-U0-R and Y-U0-S, which displayed potent Mpro inhibition and markedly enhanced antiviral activity in SARS-CoV-2-infected Calu-3 cells. Moreover, both compounds exhibited broad-spectrum antiviral activity against other human coronaviruses, and notably remained effective against the two major Nirmatrelvir-resistant strains evaluated in this study. Mechanistic studies further confirmed kinetically stable binding and time-dependent inhibition of Y-U0-R, supporting the rationale of covalent inhibitor design. These findings highlight the utility of structure-based design for the development of promising broad-spectrum anti-coronavirus agents.
Bing Ye, M. Lee, Letian Song et al.· European journal of medicina...· 0 citations
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