2. Academic Validation
  3. NPC1-regulated dynamic of clathrin-coated pits is essential for viral entry

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

  • Sci China Life Sci. 2022 Feb;65(2):341-361. doi: 10.1007/s11427-021-1929-y.
Guoli Li  # 1 2,  Bingqian Su  # 1 2,  Pengfei Fu 1 2,  Yilin Bai 3,  Guangxu Ding 1 2,  Dahua Li 1 2,  Jiang Wang 1 2 4,  Guoyu Yang 5 6 7,  Beibei Chu 8 9 10
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, China.
  • 2 Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs of the People's Republic of China, Zhengzhou, 450046, China.
  • 3 College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
  • 4 International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, China.
  • 5 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, China. [email protected].
  • 6 Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs of the People's Republic of China, Zhengzhou, 450046, China. [email protected].
  • 7 International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, China. [email protected].
  • 8 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, China. [email protected].
  • 9 Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs of the People's Republic of China, Zhengzhou, 450046, China. [email protected].
  • 10 International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, China. [email protected].
  • # Contributed equally.
PMID: 34047913 DOI: 10.1007/s11427-021-1929-y
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.

Keywords

CCP dynamics; NPC inhibition; broad-spectrum antiviral; viral entry.

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