PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2
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 an...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61759-1 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marwah Karim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3fb6a03926714188892dca645295f079 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3fb6a03926714188892dca645295f0792025-08-20T04:03:07ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-61759-1PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2Marwah Karim0Manjari Mishra1Chieh-Wen Lo2Sirle Saul3Halise Busra Cagirici4Manon Gourdelier5Luca Ghita6Amrita Ojha7Do Hoang Nhu Tran8Aditi Agrawal9Connor McGraw10Michael P. East11Karen Anbro Gammeltoft12Malaya Kumar Sahoo13Nancie A. Mooney14Gary L. Johnson15Soumita Das16Pieter Leyssen17Johan Neyts18Winston Chiu19Courtney A. Cohen20Jens Bukh21Judith Gottwein22John M. Dye23Norma Neff24Peter K. Jackson25Benjamin A. Pinsky26Tuomo Laitinen27Tatu Pantsar28Antti Poso29Fabio Zanini30Steven De Jonghe31Christopher R. M. Asquith32Shirit Einav33Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel HillDepartment of Infectious Diseases, University of CopenhagenDepartment of Pathology, Stanford University School of MedicineBaxter Laboratory, Department of Microbiology & Immunology. Stanford University School of MedicineDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel HillBiomedical & Nutritional Science, Center for Pathogen Research & Training (CPRT), University of Massachusetts-LowellKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and ChemotherapyKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and ChemotherapyKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and ChemotherapyUS Army Medical Research Institute of Infectious Diseases, Viral Immunology BranchDepartment of Infectious Diseases, University of CopenhagenDepartment of Infectious Diseases, University of CopenhagenUS Army Medical Research Institute of Infectious Diseases, Viral Immunology BranchChan Zuckerberg BiohubBaxter Laboratory, Department of Microbiology & Immunology. Stanford University School of MedicineDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversitySchool of Pharmacy, Faculty of Health Sciences, University of Eastern FinlandSchool of Pharmacy, Faculty of Health Sciences, University of Eastern FinlandSchool of Pharmacy, Faculty of Health Sciences, University of Eastern FinlandSchool of Clinical Medicine, UNSW SydneyKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and ChemotherapySchool of Pharmacy, Faculty of Health Sciences, University of Eastern FinlandDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford UniversityAbstract 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.https://doi.org/10.1038/s41467-025-61759-1 |
| spellingShingle | 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 PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 Nature Communications |
| title | PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 |
| title_full | PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 |
| title_fullStr | PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 |
| title_full_unstemmed | PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 |
| title_short | PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2 |
| title_sort | pip4k2c inhibition reverses autophagic flux impairment induced by sars cov 2 |
| url | https://doi.org/10.1038/s41467-025-61759-1 |
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