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PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.
PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2. bioRxiv : the preprint server for biology Karim, M., Mishra, M., Lo, C. W., Saul, S., Cagirici, H. B., Tran, D. H., Agrawal, A., Ghita, L., Ojha, A., East, M. P., Gammeltoft, K. A., Sahoo, M. K., Johnson, G. L., Das, S., Jochmans, D., Cohen, C. A., Gottwein, J., Dye, J., Neff, N., Pinsky, B. A., Laitinen, T., Pantsar, T., Poso, A., Zanini, F., Jonghe, S. D., Asquith, C. R., Einav, S. 2024Abstract
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.
View details for DOI 10.1101/2024.04.15.589676
View details for PubMedID 38659941
View details for PubMedCentralID PMC11042293