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<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. The emergence of viral mutations that diminish the effectiveness of current interventions underscores the importance of alternative, host-directed strategies. Here, we show that pharmacological inhibition or knockdown of host <i>N</i>-myristoyltransferase 1 (NMT1), one of the two human enzymes that mediates protein <i>N</i>-myristoylation, significantly impairs SARS-CoV-2, Vesicular Stomatitis Virus (VSV) and Respiratory syncytial virus (RSV) infections. We demonstrate the antiviral efficacy and safety of this host-directed therapeutic strategy across multiple viral tropic sites, including human lung adenocarcinoma cell lines, primary nasal epithelial cells, and human choroid plexus-cortical brain organoids. NMT1 inhibition triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, through endoplasmic reticulum and lysosomal structures, which leads to perturbed progeny virion composition and spike maturation, impairing progeny virion infectivity.</p>

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Inhibition of host N-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月11日

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  • Saber H. Saber,
  • Nyakuoy Yak,
  • Konstantin Dolski,
  • Sanna Mäki,
  • Lev Levanov,
  • Levina A. Willenbrink,
  • Julian D. J. Sng,
  • Mohammed R. Shaker,
  • Sean D. Morrison,
  • Huiwen Zheng,
  • Selin Pars,
  • Giovanni Pietrogrande,
  • Yih Tyng Bong,
  • Tania Vane-Tempest,
  • Teemu Smura,
  • Tomas Strandin,
  • Ravi Ojha,
  • Ravi Kant,
  • Janika Ruuska,
  • Francesco Topi,
  • Diana Vaskiv,
  • Lauri Kareinen,
  • Tobias Binder,
  • Siyuan Lu,
  • Matthias Floetenmeyer,
  • Bahaa Al-mhanawi,
  • Yanshan Zhu,
  • Tarja Sironen,
  • Gert Hoy Talbo,
  • Kirsty R. Short,
  • Wouter W. Kallemeijn,
  • Roberto Solari,
  • Jessica Mar,
  • Edward W. Tate,
  • Ashley J. van Waardenberg,
  • Olli Vapalahti,
  • Ernst Wolvetang,
  • Giuseppe Balistreri,
  • Merja Joensuu

摘要

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. The emergence of viral mutations that diminish the effectiveness of current interventions underscores the importance of alternative, host-directed strategies. Here, we show that pharmacological inhibition or knockdown of host N-myristoyltransferase 1 (NMT1), one of the two human enzymes that mediates protein N-myristoylation, significantly impairs SARS-CoV-2, Vesicular Stomatitis Virus (VSV) and Respiratory syncytial virus (RSV) infections. We demonstrate the antiviral efficacy and safety of this host-directed therapeutic strategy across multiple viral tropic sites, including human lung adenocarcinoma cell lines, primary nasal epithelial cells, and human choroid plexus-cortical brain organoids. NMT1 inhibition triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, through endoplasmic reticulum and lysosomal structures, which leads to perturbed progeny virion composition and spike maturation, impairing progeny virion infectivity.