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

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 Jonghe, Christopher R. M. Asquith and Shirit Einav ()
Additional contact information
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
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
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
Judith Gottwein: 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
Tuomo Laitinen: University of Eastern Finland
Tatu Pantsar: University of Eastern Finland
Antti Poso: University of Eastern Finland
Fabio Zanini: UNSW Sydney
Steven Jonghe: Laboratory of Virology and Chemotherapy
Christopher R. M. Asquith: University of Eastern Finland
Shirit Einav: Stanford University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61759-1

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