tetano
Editor, Senior Moderator
Nat Commun
. 2025 Jul 10;16(1):6397.
doi: 10.1038/s41467-025-61759-1. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2
Marwah Karim[SUP] #[/SUP][SUP] 1 [/SUP], Manjari Mishra[SUP] #[/SUP][SUP] 1 [/SUP], Chieh-Wen Lo[SUP] 1 [/SUP], Sirle Saul[SUP] 1 [/SUP], Halise Busra Cagirici[SUP] 1 [/SUP], Manon Gourdelier[SUP] 1 [/SUP], Luca Ghita[SUP] 1 [/SUP], Amrita Ojha[SUP] 1 [/SUP], Do Hoang Nhu Tran[SUP] 1 [/SUP], Aditi Agrawal[SUP] 1 [/SUP], Connor McGraw[SUP] 1 [/SUP], Michael P East[SUP] 2 [/SUP], Karen Anbro Gammeltoft[SUP] 3 4 5 [/SUP], Malaya Kumar Sahoo[SUP] 6 [/SUP], Nancie A Mooney[SUP] 7 [/SUP], Gary L Johnson[SUP] 2 8 [/SUP], Soumita Das[SUP] 9 [/SUP], Pieter Leyssen[SUP] 10 [/SUP], Johan Neyts[SUP] 10 [/SUP], Winston Chiu[SUP] 10 [/SUP], Courtney A Cohen[SUP] 11 [/SUP], Jens Bukh[SUP] 3 4 5 [/SUP], Judith Gottwein[SUP] 3 4 5 [/SUP], John M Dye[SUP] 11 [/SUP], Norma Neff[SUP] 12 [/SUP], Peter K Jackson[SUP] 7 [/SUP], Benjamin A Pinsky[SUP] 1 6 [/SUP], Tuomo Laitinen[SUP] 13 [/SUP], Tatu Pantsar[SUP] 13 [/SUP], Antti Poso[SUP] 13 [/SUP], Fabio Zanini[SUP] 14 15 16 [/SUP], Steven De Jonghe[SUP] 10 [/SUP], Christopher R M Asquith[SUP] 13 [/SUP], Shirit Einav[SUP] 17 18 19 [/SUP]
Affiliations
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.
. 2025 Jul 10;16(1):6397.
doi: 10.1038/s41467-025-61759-1. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2
Marwah Karim[SUP] #[/SUP][SUP] 1 [/SUP], Manjari Mishra[SUP] #[/SUP][SUP] 1 [/SUP], Chieh-Wen Lo[SUP] 1 [/SUP], Sirle Saul[SUP] 1 [/SUP], Halise Busra Cagirici[SUP] 1 [/SUP], Manon Gourdelier[SUP] 1 [/SUP], Luca Ghita[SUP] 1 [/SUP], Amrita Ojha[SUP] 1 [/SUP], Do Hoang Nhu Tran[SUP] 1 [/SUP], Aditi Agrawal[SUP] 1 [/SUP], Connor McGraw[SUP] 1 [/SUP], Michael P East[SUP] 2 [/SUP], Karen Anbro Gammeltoft[SUP] 3 4 5 [/SUP], Malaya Kumar Sahoo[SUP] 6 [/SUP], Nancie A Mooney[SUP] 7 [/SUP], Gary L Johnson[SUP] 2 8 [/SUP], Soumita Das[SUP] 9 [/SUP], Pieter Leyssen[SUP] 10 [/SUP], Johan Neyts[SUP] 10 [/SUP], Winston Chiu[SUP] 10 [/SUP], Courtney A Cohen[SUP] 11 [/SUP], Jens Bukh[SUP] 3 4 5 [/SUP], Judith Gottwein[SUP] 3 4 5 [/SUP], John M Dye[SUP] 11 [/SUP], Norma Neff[SUP] 12 [/SUP], Peter K Jackson[SUP] 7 [/SUP], Benjamin A Pinsky[SUP] 1 6 [/SUP], Tuomo Laitinen[SUP] 13 [/SUP], Tatu Pantsar[SUP] 13 [/SUP], Antti Poso[SUP] 13 [/SUP], Fabio Zanini[SUP] 14 15 16 [/SUP], Steven De Jonghe[SUP] 10 [/SUP], Christopher R M Asquith[SUP] 13 [/SUP], Shirit Einav[SUP] 17 18 19 [/SUP]
Affiliations
- PMID: 40640184
- DOI: 10.1038/s41467-025-61759-1
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.