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

Author

Listed:
  • Marwah Karim

    (Stanford University)

  • Manjari Mishra

    (Stanford University)

  • Chieh-Wen Lo

    (Stanford University)

  • Sirle Saul

    (Stanford University)

  • Halise Busra Cagirici

    (Stanford University)

  • Manon Gourdelier

    (Stanford University)

  • Luca Ghita

    (Stanford University)

  • Amrita Ojha

    (Stanford University)

  • Do Hoang Nhu Tran

    (Stanford University)

  • Aditi Agrawal

    (Stanford University)

  • Connor McGraw

    (Stanford University)

  • Michael P. East

    (University of North Carolina at Chapel Hill)

  • Karen Anbro Gammeltoft

    (University of Copenhagen
    Copenhagen University Hospital–Hvidovre
    University of Copenhagen)

  • Malaya Kumar Sahoo

    (Stanford University School of Medicine)

  • Nancie A. Mooney

    (Department of Microbiology & Immunology. Stanford University School of Medicine)

  • Gary L. Johnson

    (University of North Carolina at Chapel Hill
    University of North Carolina School of Medicine)

  • Soumita Das

    (University of Massachusetts-Lowell)

  • Pieter Leyssen

    (Laboratory of Virology and Chemotherapy)

  • Johan Neyts

    (Laboratory of Virology and Chemotherapy)

  • Winston Chiu

    (Laboratory of Virology and Chemotherapy)

  • Courtney A. Cohen

    (Viral Immunology Branch)

  • Jens Bukh

    (University of Copenhagen
    Copenhagen University Hospital–Hvidovre
    University of Copenhagen)

  • Judith Gottwein

    (University of Copenhagen
    Copenhagen University Hospital–Hvidovre
    University of Copenhagen)

  • John M. Dye

    (Viral Immunology Branch)

  • Norma Neff

    (Chan Zuckerberg Biohub)

  • Peter K. Jackson

    (Department of Microbiology & Immunology. Stanford University School of Medicine)

  • Benjamin A. Pinsky

    (Stanford University
    Stanford University School of Medicine)

  • Tuomo Laitinen

    (University of Eastern Finland)

  • Tatu Pantsar

    (University of Eastern Finland)

  • Antti Poso

    (University of Eastern Finland)

  • Fabio Zanini

    (UNSW Sydney
    UNSW Sydney
    UNSW Sydney)

  • Steven Jonghe

    (Laboratory of Virology and Chemotherapy)

  • Christopher R. M. Asquith

    (University of Eastern Finland)

  • Shirit Einav

    (Stanford University
    Chan Zuckerberg Biohub
    Stanford University)

Abstract

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.

Suggested Citation

  • 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 & , 2025. "PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61759-1
    DOI: 10.1038/s41467-025-61759-1
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