2. Academic Validation
  3. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

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

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.
PMID: 38659941 DOI: 10.1101/2024.04.15.589676
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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