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Cited by 16SARS-CoV-2 and COVID-19 ResearchAutophagy in Disease and TherapyCellular transport and secretion

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

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Karim, Marwah, Mishra, Manjari, Lo, Chieh-Wen, Saul, Sirle, Cagirici, Halise Busra, Gourdelier, Manon, Ghita, Luca, Ojha, Amrita, Tran, Do Hoang Nhu, Agrawal, Aditi, McGraw, Connor, East, Michael P., Gammeltoft, Karen Anbro, Sahoo, Malaya Kumar, Mooney, Nancie A., Johnson, Gary L., Das, Soumita, Leyssen, Pieter, Neyts, Johan, Chiu, Winston, Cohen, Courtney A., Bukh, Jens, Gottwein, Judith, Dye, John M., Neff, Norma, Jackson, Peter K., Pinsky, Benjamin A., Laitinen, Tuomo, Pantsar, Tatu, Poso, Antti, Zanini, Fabio, De Jonghe, Steven, Asquith, Christopher R. M., Einav, Shirit·2025·Nature Communications
DOI 10.1038/s41467-025-61759-1PMC PMC12246422

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Abstract

Abstract In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered 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 revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this 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 inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.

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Metadata

Authors
Karim, M., Mishra, M., Lo, C.-W., Saul, S., Cagirici, H. B., Gourdelier, M., Ghita, L., Ojha, A., Tran, D. H. N., Agrawal, A., McGraw, C., East, M. P., Gammeltoft, K. A., Sahoo, M. K., Mooney, N. A., Johnson, G. L., Das, S., Leyssen, P., Neyts, J., Chiu, W., Cohen, C. A., Bukh, J., Gottwein, J., Dye, J. M., Neff, N., Jackson, P. K., Pinsky, B. A., Laitinen, T., Pantsar, T., Poso, A., Zanini, F., De Jonghe, S., Asquith, C. R. M., & Einav, S.
Affiliations
  • Stanford Medicine (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Copenhagen (DK)
  • University of Massachusetts Lowell (US)
  • Rega Institute for Medical Research (BE)
  • United States Army Medical Research Institute of Infectious Diseases (US)
  • Chan Zuckerberg Biohub San Francisco (US)
  • University of Eastern Finland (FI)
  • UNSW Sydney (AU)
Corresponding author
Einav, Shirit
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-07-10
Volume
16
Issue
1
Pages
6397-6397
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-61759-1
PMC
PMC12246422
OpenAlex
W4412166165
Cited by
16
References
4
Citations by year
2026: 13 · 2025: 2
FWCI
11.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lirias (submittedVersion, other-oa)
Funders
  • United States Department of Defense | Defense Threat Reduction Agency (HDTRA11810039)
  • U.S. Department of Defense (W81XWH2210283, W81XWH-16-1-0691)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
PIKfyve, SARS-CoV-2, small-molecule antivirals, viral protein degradation, viral RNA replication, broad-spectrum antivirals

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