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

Ilyas Khan, Sunan Li, Lihong Tao, Chong Wang, Bowei Ye, Huiyu Li, Xiaoyang Liu, Iqbal Ahmad, Wenqiang Su, Gongxun Zhong, Zhiyuan Wen, Jinliang Wang, Rong-Hong Hua, Ao Ma, Jie Liang, Xiao-Peng Wan (), Zhi-Gao Bu () and Yong-Hui Zheng ()
Additional contact information
Ilyas Khan: Chinese Academy of Agricultural Sciences
Sunan Li: Chinese Academy of Agricultural Sciences
Lihong Tao: Chinese Academy of Agricultural Sciences
Chong Wang: Chinese Academy of Agricultural Sciences
Bowei Ye: The University of Illinois Chicago
Huiyu Li: The University of Illinois Chicago
Xiaoyang Liu: Chinese Academy of Agricultural Sciences
Iqbal Ahmad: Chinese Academy of Agricultural Sciences
Wenqiang Su: Chinese Academy of Agricultural Sciences
Gongxun Zhong: Chinese Academy of Agricultural Sciences
Zhiyuan Wen: Chinese Academy of Agricultural Sciences
Jinliang Wang: Chinese Academy of Agricultural Sciences
Rong-Hong Hua: Chinese Academy of Agricultural Sciences
Ao Ma: The University of Illinois Chicago
Jie Liang: The University of Illinois Chicago
Xiao-Peng Wan: Chinese Academy of Agricultural Sciences
Zhi-Gao Bu: Chinese Academy of Agricultural Sciences
Yong-Hui Zheng: The University of Illinois Chicago

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44504-4

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