Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1

  • Nat Commun. 2024 Jan 2;15(1):162. doi: 10.1038/s41467-023-44504-4.
Ilyas Khan  1 ,  Sunan Li  1 ,  Lihong Tao  1 ,  Chong Wang  1 ,  Bowei Ye  2 ,  Huiyu Li  2 ,  Xiaoyang Liu  1 ,  Iqbal Ahmad  1 ,  Wenqiang Su  1 ,  Gongxun Zhong  1 ,  Zhiyuan Wen  1 ,  Jinliang Wang  1 ,  Rong-Hong Hua  1 ,  Ao Ma  2 ,  Jie Liang  2 ,  Xiao-Peng Wan  3 ,  Zhi-Gao Bu  4 ,  Yong-Hui Zheng  5
Affiliations
  • 1. State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
  • 2. Center for Bioinformatics and Quantitative Biology, Richard and Loan Hill Department of Biomedical Engineering, The University of Illinois Chicago, Chicago, IL, 60607, USA.
  • 3. State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China. [email protected].
  • 4. State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China. [email protected].
  • 5. Department of Microbiology and Immunology, The University of Illinois Chicago, Chicago, IL, 60612, USA. [email protected].
PMID: 38167417 DOI: 10.1038/s41467-023-44504-4
Abstract

SARS-CoV-2 and Filovirus enter cells via the cell surface angiotensin-converting enzyme 2 (ACE2) or the late-endosome Niemann-Pick C1 (NPC1) as a receptor. Here, we screened 974 natural compounds and identified Tubeimosides I, II, and III as pan-coronavirus and Filovirus entry inhibitors that target NPC1. Using in-silico, biochemical, and genomic approaches, we provide evidence that NPC1 also binds SARS-CoV-2 spike (S) protein on the receptor-binding domain (RBD), which is blocked by Tubeimosides. Importantly, NPC1 strongly promotes productive SARS-CoV-2 entry, which we propose is due to its influence on fusion in late endosomes. The Tubeimosides' Antiviral activity and NPC1 function are further confirmed by Infection with SARS-CoV-2 variants of concern (VOC), SARS-CoV, and MERS-CoV. Thus, NPC1 is a critical entry co-factor for highly pathogenic human coronaviruses (HCoVs) in the late endosomes, and Tubeimosides hold promise as a new countermeasure for these HCoVs and filoviruses.

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