Three effective countermeasures have been established: structure-based optimization of Mpro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies to combat emerging resistant SARS-CoV-2 variants.
Abstract
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.
Evaluating the drug resistance mechanisms of multiple SARS-CoV-2 non-structural proteins, including the main protease and the RNA-dependent RNA polymerase, as well as PLPro, EndoU, and Mac1, which contribute to viral replication and counter host innate immune responses are discussed.
This review covers 2020-2026 advances in CA-targeted drug discovery: high-resolution CA structures; allosteric regulation by host metabolite IP6; medicinal chemistry optimization of PF74 derivatives via scaffold hopping and conformational restriction to enhance potency and metabolic stability; the development and clini...
Yu-Ya Li, Mei Wang, Lin Sun et al.· European journal of medicina...· 0 citations
Main protease (Mpro) enzyme of Severe Acute Respiratory Syndrome Coronavirus
2 (SARS-CoV-2) cleaves polyprotein pp1a and pp1ab at 11 sites, producing essential proteins
of viral machinery, and possesses a conserved Cys145-His41 catalytic dyad. While different
mutated strains of this virus are being identified, the...
Anand Kumar Pandey, S. Rathore· Current Biological Sciences· 0 citations
The findings provide mechanistic insights into a key allosteric mechanism for Mpro inhibition but also provide a promising chemical scaffold for further development as an Mpro-targeting inhibitor.
Quanling Zhang, Tingting Wen, Meng-Si Li et al.· Drug Discoveries & Therapeut...· 0 citations
This Account summarizes the group's effort to convert PLpro from a challenging target into a tractable antiviral drug-discovery platform and illustrates how integrated assay development, structural biology, medicinal chemistry, pharmacology, virology, and resistance analysis can transform a challenging viral deubiquiti...
Jun Wang, Kan Li, Bin Tan· Accounts of Chemical Researc...· 0 citations
Nirmatrelvir, the active antiviral component of Paxlovid®, was evaluated for potency against 20 genetically diverse and clinically relevant SARS-CoV-2 variants circulating between 2020 and 2024. Robust in vitro antiviral activity was demonstrated against all tested variants, with only modest reductions in susceptibilit...
Irina Yurgelonis, Devendra K. Rai, Jonathan T. Lee et al.· Antiviral Research· 0 citations
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