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<p>Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused significant global loss and social disruption. Although large-scale vaccination campaigns and naturally acquired immunity have reduced viral transmission, the rapid evolution of the viral genome—driven by the lack of proofreading during replication—continues to pose a major public health threat. The current SARS-CoV-2 main protease inhibitor (Mpro), Paxlovid, substantially lowers hospitalization rates but is associated with adverse effects and drug–drug interactions with many medications. To discover more effective and safer treatments, we conducted a large-scale virtual screening to identify novel structural scaffolds targeting viral Mpro. This effort yielded a series of spiropyrrolidinoxindole derivative hits with promising low-micromolar inhibitory activity. Through preliminary analysis of the structure-activity relationship and proposed binding conformations, our findings provide a basis for rational structural optimization and may facilitate the development of potent, safer spiropyrrolidinoxindole-based therapeutics against severe COVID-19.</p>

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Identification of spiropyrrolidinoxindoles as SARS-CoV-2 main protease inhibitor hits from virtual screening

  • 期刊论文

  • 发表日期：

    2026年6月19日

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  • Chao-Yu Chen,
  • Li-Wen Lee,
  • Ting-Yao Wang,
  • Yuan-Yuan Jiang,
  • Chia-Hung Han,
  • Cheng-Chih Hsieh,
  • Ming-Szu Hung,
  • Hui-Fen Liao,
  • Ching-Yuan Wu,
  • Jrhau Lung

摘要

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused significant global loss and social disruption. Although large-scale vaccination campaigns and naturally acquired immunity have reduced viral transmission, the rapid evolution of the viral genome—driven by the lack of proofreading during replication—continues to pose a major public health threat. The current SARS-CoV-2 main protease inhibitor (Mpro), Paxlovid, substantially lowers hospitalization rates but is associated with adverse effects and drug–drug interactions with many medications. To discover more effective and safer treatments, we conducted a large-scale virtual screening to identify novel structural scaffolds targeting viral Mpro. This effort yielded a series of spiropyrrolidinoxindole derivative hits with promising low-micromolar inhibitory activity. Through preliminary analysis of the structure-activity relationship and proposed binding conformations, our findings provide a basis for rational structural optimization and may facilitate the development of potent, safer spiropyrrolidinoxindole-based therapeutics against severe COVID-19.