PIP4K2C抑制可逆转由SARS-CoV-2诱导的自噬通量损伤。

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

作者信息

Karim Marwah, Mishra Manjari, Lo Chieh-Wen, Saul Sirle, Cagirici Halise Busra, Gourdelier Manon, Ghita Luca, Ojha Amrita, Tran Do Hoang Nhu, Agrawal Aditi, McGraw Connor, East Michael P, Gammeltoft Karen Anbro, Sahoo Malaya Kumar, Mooney Nancie A, Johnson Gary L, Das Soumita, Leyssen Pieter, Neyts Johan, Chiu Winston, Cohen Courtney A, Bukh Jens, Gottwein Judith, Dye John M, Neff Norma, Jackson Peter K, Pinsky Benjamin A, Laitinen Tuomo, Pantsar Tatu, Poso Antti, Zanini Fabio, De Jonghe Steven, Asquith Christopher R M, Einav Shirit

机构信息

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

出版信息

Nat Commun. 2025 Jul 10;16(1):6397. doi: 10.1038/s41467-025-61759-1.

DOI:10.1038/s41467-025-61759-1

PMID:40640184

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12246422/

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.

摘要

在寻找广谱抗病毒药物的过程中，我们发现了一种小分子抑制剂RMC-113，它能有效抑制多种RNA病毒在人肺类器官中的复制，包括SARS-CoV-2。我们证明了RMC-113对脂质激酶PIP4K2C和PIKfyve的选择性抑制作用，以及其可点击类似物的靶点结合作用。脂质组学分析揭示了RMC-113对SARS-CoV-2诱导的磷酸肌醇特征的改变，并将其抗病毒作用与功能性PIP4K2C和PIKfyve抑制联系起来。我们确定了PIP4K2C在SARS-CoV-2进入、RNA复制和组装/释放中的作用，验证了它是一个可成药的抗病毒靶点。整合蛋白质组学、单细胞转录组学和功能分析表明，PIP4K2C与SARS-CoV-2非结构蛋白6结合，并调节病毒诱导的自噬通量受损。通过逆转自噬通量受损来促进病毒蛋白降解是RMC-113的抗病毒作用机制。这些发现揭示了通过PIP4K2C（一种研究较少的激酶）对病毒诱导的自噬调节，并提出双重抑制PIP4K2C和PIKfyve作为对抗新兴病毒的候选策略。