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<p>In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Lipidomics analysis reveals alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and links its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We identify PIP4K2C’s roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays, reveals that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced autophagic flux impairment. Promoting viral protein degradation by reversing autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual PIP4K2C and PIKfyve inhibition as a candidate strategy to combat emerging viruses.</p>

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PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Marwah Karim,
  • Manjari Mishra,
  • Chieh-Wen Lo,
  • Sirle Saul,
  • Halise Busra Cagirici,
  • Manon Gourdelier,
  • Luca Ghita,
  • Amrita Ojha,
  • Do Hoang Nhu Tran,
  • Aditi Agrawal,
  • Connor McGraw,
  • Michael P. East,
  • Karen Anbro Gammeltoft,
  • Malaya Kumar Sahoo,
  • Nancie A. Mooney,
  • Gary L. Johnson,
  • Soumita Das,
  • Pieter Leyssen,
  • Johan Neyts,
  • Winston Chiu,
  • Courtney A. Cohen,
  • Jens Bukh,
  • Judith Gottwein,
  • John M. Dye,
  • Norma Neff,
  • Peter K. Jackson,
  • Benjamin A. Pinsky,
  • Tuomo Laitinen,
  • Tatu Pantsar,
  • Antti Poso,
  • Fabio Zanini,
  • Steven De Jonghe,
  • Christopher R. M. Asquith,
  • Shirit Einav

摘要

In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Lipidomics analysis reveals alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and links its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We identify PIP4K2C’s roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays, reveals that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced autophagic flux impairment. Promoting viral protein degradation by reversing autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual PIP4K2C and PIKfyve inhibition as a candidate strategy to combat emerging viruses.