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<p>The SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) is a cysteine protease that cleaves viral polyproteins and antagonizes the host immune response during viral replication. <b>Jun12682</b> and PF-07957472 are the first-in-class PL<sup>pro</sup> inhibitors showing potent in vivo antiviral efficacy in mouse models. In this study, we characterize naturally occurring mutations at residues located at the drug-binding site of <b>Jun12682</b>. The results reveal several PL<sup>pro</sup> mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PL<sup>pro</sup>. The physiological relevance of the identified drug-resistant mutants, including E167G and Q269H, is validated through independent serial viral passage experiments. Molecular dynamics simulations and perturbative free energy calculations show that drug-resistant PL<sup>pro</sup> mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PL<sup>pro</sup> inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PL<sup>pro</sup> inhibitors.</p>

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Identification of naturally occurring drug-resistant mutations of SARS-CoV-2 papain-like protease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月16日

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  • Haozhou Tan,
  • Qianru Zhang,
  • Kyriakos Georgiou,
  • Siyu Zhang,
  • Kan Li,
  • George Lambrinidis,
  • Antonios Kolocouris,
  • Xufang Deng,
  • Jun Wang

摘要

The SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves viral polyproteins and antagonizes the host immune response during viral replication. Jun12682 and PF-07957472 are the first-in-class PLpro inhibitors showing potent in vivo antiviral efficacy in mouse models. In this study, we characterize naturally occurring mutations at residues located at the drug-binding site of Jun12682. The results reveal several PLpro mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PLpro. The physiological relevance of the identified drug-resistant mutants, including E167G and Q269H, is validated through independent serial viral passage experiments. Molecular dynamics simulations and perturbative free energy calculations show that drug-resistant PLpro mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PLpro inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PLpro inhibitors.