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. 2021 May 27;65(2):341–361. doi: 10.1007/s11427-021-1929-y

NPC1-regulated dynamic of clathrin-coated pits is essential for viral entry

Guoli Li 1,2,#, Bingqian Su 1,2,#, Pengfei Fu 1,2, Yilin Bai 4, Guangxu Ding 1,2, Dahua Li 1,2, Jiang Wang 1,2,3, Guoyu Yang 1,2,3,✉, Beibei Chu 1,2,3,✉
PMCID: PMC8160554  PMID: 34047913

Abstract

Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread. Therefore, the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial. Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) infection, we found that U18666A, a specific inhibitor of Niemann-Pick C1 (NPC1), is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma membrane, thereby inhibiting the dynamics of clathrin-coated pits (CCPs), which are indispensable for clathrin-mediated endocytosis. Significantly, exogenous cholesterol can complement the dynamics of CCPs, leading to efficient viral entry and infectivity. Administration of U18666A improves the survival and pathology of PRV- and influenza A virus-infected mice. Thus, our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity, indicating a potential new therapeutic strategy against SARS-CoV-2, as well as other emerging viruses.

Supporting Information

The supporting information is available online at 10.1007/s11427-021-1929-y. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

Keywords: broad-spectrum antiviral, NPC inhibition, CCP dynamics, viral entry

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Acknowledgements

We thank Bao-Liang Song (Wuhan University, China) for providing CHO-K1 and CT43 cells; Ke-Gong Tian (Henan Agricultural University, China) for providing PRV HN1201; and Shao-Bo Xiao (Huazhong Agricultural University, China) for providing MHV A59.

Compliance and ethics The author(s) declare that they have no conflict of interest. The animal experimental procedure was approved by the Ethics Committtee of Henan Agricultural University.

Footnotes

Contributed equally to this work

Contributor Information

Guoyu Yang, Email: haubiochem@163.com.

Beibei Chu, Email: chubeibei@henau.edu.cn.

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