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<p>Anecdotal reports about smoking that might prevent SARS-CoV-2 infection inspire the search for nicotine and its pyrolysis products as inhibitors of the SARS-CoV-2 main protease (M<sup>Pro</sup>). This effort leads to the discovery of 3-vinylpyridine as an M<sup>Pro</sup> inhibitor. 3-Vinylpyridine resembles part of nirmatrelvir in binding to M<sup>Pro</sup> but does not involve a critical interaction with residue E166, whose mutation has led to resistance to nirmatrelvir. Integration of the two molecules, followed by a medicinal chemistry campaign, produces several molecules with better in vitro potency than nirmatrelvir. Two lead molecules, YR-C-136 and SR-B-103, display better pharmacokinetic characteristics than nirmatrelvir in virus-challenged male mice and much better antiviral efficacy in virus-challenged female mice. Both molecules maintain high potency in inhibiting the nirmatrelvir-resistant M<sup>Pro</sup> (E166V/L50F) variant. They also exhibit a broad and highly potent antiviral spectrum against most pathogenic coronaviruses. With high in vivo potency, both molecules are potentially standalone pan-antivirals for coronaviruses and may serve as countermeasures for future coronavirus outbreaks.</p>

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From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月14日

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  • Kaustav Khatua,
  • Sandeep Atla,
  • Demonta Coleman,
  • Lauren R. Blankenship,
  • Yugendar R. Alugubelli,
  • Veerabhadra Vulupala,
  • Xuejiao Shirley Guo,
  • Hongjie Xia,
  • Birte K. Kalveram,
  • David H. Walker,
  • Brett L. Hurst,
  • Sathish Kumar,
  • Chia-Chuan D. Cho,
  • Shivangi Sharma,
  • Kai Yang,
  • Dorsa Rabie,
  • Satyanarayana Nyalata,
  • Benjamin W. Neuman,
  • Xuping Xie,
  • Shiqing Xu,
  • Wenshe Ray Liu

摘要

Anecdotal reports about smoking that might prevent SARS-CoV-2 infection inspire the search for nicotine and its pyrolysis products as inhibitors of the SARS-CoV-2 main protease (MPro). This effort leads to the discovery of 3-vinylpyridine as an MPro inhibitor. 3-Vinylpyridine resembles part of nirmatrelvir in binding to MPro but does not involve a critical interaction with residue E166, whose mutation has led to resistance to nirmatrelvir. Integration of the two molecules, followed by a medicinal chemistry campaign, produces several molecules with better in vitro potency than nirmatrelvir. Two lead molecules, YR-C-136 and SR-B-103, display better pharmacokinetic characteristics than nirmatrelvir in virus-challenged male mice and much better antiviral efficacy in virus-challenged female mice. Both molecules maintain high potency in inhibiting the nirmatrelvir-resistant MPro (E166V/L50F) variant. They also exhibit a broad and highly potent antiviral spectrum against most pathogenic coronaviruses. With high in vivo potency, both molecules are potentially standalone pan-antivirals for coronaviruses and may serve as countermeasures for future coronavirus outbreaks.