PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 PMID: 38659941

ADC Targets in Oncology

2026-04-10

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

bioRxiv. 2024 Apr 17:2024.04.15.589676. doi: 10.1101/2024.04.15.589676.

Marwah Karim ¹ , Manjari Mishra ¹ , Chieh-Wen Lo ¹ , Sirle Saul ¹ , Halise Busra Cagirici ¹ , Do Hoang Nhu Tran ¹ , Aditi Agrawal ¹ , Luca Ghita ¹ , Amrita Ojha ¹ , Michael P East ² , Karen Anbro Gammeltoft ³ ⁴ ⁵ , Malaya Kumar Sahoo ⁶ , Gary L Johnson ² , Soumita Das ⁷ , Dirk Jochmans ⁸ , Courtney A Cohen ⁹ , Judith Gottwein ³ ⁴ ⁵ , John Dye ⁹ , Norma Neff ¹⁰ , Benjamin A Pinsky ¹ ⁶ , Tuomo Laitinen ¹¹ , Tatu Pantsar ¹¹ , Antti Poso ¹¹ , Fabio Zanini ¹² ¹³ ¹⁴ , Steven De Jonghe ⁸ , Christopher R M Asquith ¹¹ , Shirit Einav ¹ ¹⁰ ¹⁵

Affiliations

1. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
2. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3. Department of Infectious Diseases, University of Copenhagen, Denmark. Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen.
4. University Hospital-Hvidovre, Hvidovre, Denmark.
5. Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
6. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
7. Biomedical & Nutritional Science, Center for Pathogen Research & Training (CPRT), University of Massachusetts-Lowell, USA.
8. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
9. US Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch, Frederick, Maryland, USA.
10. Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
11. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Finland.
12. School of Clinical Medicine, UNSW Sydney, Sydney, New South Wales, Australia.
13. Cellular Genomics Futures Institute, UNSW Sydney, Sydney, New South Wales, Australia.
14. Evolution and Ecology Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
15. Department of Microbiology and Immunology, Stanford University, CA, USA.

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.