Author Reply to Peer Reviews of PI3P dependent regulation of cell size and autophagy by phosphatidylinositol 5-phosphate 4-kinase

Ghosh, Avishek; Venugopal, Aishwarya; Shinde, Dhananjay; Sharma, Sanjeev; Krishnan, Meera; Mathre, Swarna; Krishnan, Harini; Raghu, Padinjat

doi:10.15252/rc.2023193724

2023

DOI: 10.15252/rc.2023193724

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Author Reply to Peer Reviews of PI3P dependent regulation of cell size and autophagy by phosphatidylinositol 5-phosphate 4-kinase

Avishek Ghosh

Aishwarya Venugopal

Dhananjay Shinde

et al.

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

Karim,

Mishra,

et al. 2024

Preprint

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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 PIP4K2Cs 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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PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

Karim,

Mishra,

et al. 2024

Preprint

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Author Reply to Peer Reviews of PI3P dependent regulation of cell size and autophagy by phosphatidylinositol 5-phosphate 4-kinase

Cited by 1 publication

References 0 publications

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

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

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