2026-04-21 スタンフォード大学
＜関連情報＞
- https://news.stanford.edu/stories/2026/04/antiviral-drug-development-research
- https://www.nature.com/articles/s41467-025-61759-1
- https://www.jci.org/articles/view/170236
PIP4K2C阻害はSARS-CoV-2によって誘発されるオートファジーフラックス障害を逆転させる PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2
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,… Shirit Einav
Nature Communications Published:10 July 2025
DOI:https://doi.org/10.1038/s41467-025-61759-1
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.
広範囲のウイルスに有効な抗ウイルス剤で、次のウイルスの脅威に備える Preparing for the next viral threat with broad-spectrum antivirals
Marwah Karim, Chieh-Wen Lo, and Shirit Einav
The Journal of Clinical Investigation Published: June 1, 2023
DOI:https://doi.org/10.1172/JCI170236
Abstract
There is a large global unmet need for the development of countermeasures to combat hundreds of viruses known to cause human disease and for the establishment of a therapeutic portfolio for future pandemic preparedness. Most approved antiviral therapeutics target proteins encoded by a single virus, providing a narrow spectrum of coverage. This, combined with the slow pace and high cost of drug development, limits the scalability of this direct-acting antiviral (DAA) approach. Here, we summarize progress and challenges in the development of broad-spectrum antivirals that target either viral elements (proteins, genome structures, and lipid envelopes) or cellular proviral factors co-opted by multiple viruses via newly discovered compounds or repurposing of approved drugs. These strategies offer new means for developing therapeutics against both existing and emerging viral threats that complement DAAs.
