Nature Communications (Jul 2025)
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 De Jonghe,
- Christopher R. M. Asquith,
- Shirit Einav
Affiliations
- Marwah Karim
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Manjari Mishra
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Chieh-Wen Lo
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Sirle Saul
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Halise Busra Cagirici
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Manon Gourdelier
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Luca Ghita
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Amrita Ojha
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Do Hoang Nhu Tran
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Aditi Agrawal
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Connor McGraw
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Michael P. East
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill
- Karen Anbro Gammeltoft
- Department of Infectious Diseases, University of Copenhagen
- Malaya Kumar Sahoo
- Department of Pathology, Stanford University School of Medicine
- Nancie A. Mooney
- Baxter Laboratory, Department of Microbiology & Immunology. Stanford University School of Medicine
- Gary L. Johnson
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill
- Soumita Das
- Biomedical & Nutritional Science, Center for Pathogen Research & Training (CPRT), University of Massachusetts-Lowell
- Pieter Leyssen
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
- Johan Neyts
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
- Winston Chiu
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
- Courtney A. Cohen
- US Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch
- Jens Bukh
- Department of Infectious Diseases, University of Copenhagen
- Judith Gottwein
- Department of Infectious Diseases, University of Copenhagen
- John M. Dye
- US Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch
- Norma Neff
- Chan Zuckerberg Biohub
- Peter K. Jackson
- Baxter Laboratory, Department of Microbiology & Immunology. Stanford University School of Medicine
- Benjamin A. Pinsky
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- Tuomo Laitinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
- Tatu Pantsar
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
- Antti Poso
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
- Fabio Zanini
- School of Clinical Medicine, UNSW Sydney
- Steven De Jonghe
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
- Christopher R. M. Asquith
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
- Shirit Einav
- Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University
- DOI
- https://doi.org/10.1038/s41467-025-61759-1
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
