Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1.
Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1.
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DOI：
10.1038/s41467-023-44504-4
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发表时间：
2024-01-02
影响因子：
16.6
通讯作者：
Zheng, Yong-Hui
中科院分区：
文献类型：
--
作者：
Khan, Ilyas;Li, Sunan;Tao, Lihong;Wang, Chong;Ye, Bowei;Li, Huiyu;Liu, Xiaoyang;Ahmad, Iqbal;Su, Wenqiang;Zhong, Gongxun;Wen, Zhiyuan;Wang, Jinliang;Hua, Rong-Hong;Ma, Ao;Liang, Jie;Wan, Xiao-Peng;Bu, Zhi-Gao;Zheng, Yong-Hui
新冠病毒（SARS-CoV - 2）和丝状病毒通过细胞表面的血管紧张素转换酶2（ACE2）或晚期内体的尼曼 - 匹克C1（NPC1）作为受体进入细胞。在此，我们筛选了974种天然化合物，并确定土贝母苷I、II和III是靶向NPC1的泛冠状病毒和丝状病毒进入抑制剂。通过计算机模拟、生化和基因组方法，我们提供的证据表明NPC1还在受体结合域（RBD）上结合新冠病毒刺突（S）蛋白，这一过程可被土贝母苷阻断。重要的是，NPC1强烈促进新冠病毒的有效进入，我们认为这是由于它对晚期内体融合的影响。通过感染受关注的新冠病毒变异株（VOC）、新冠病毒（SARS - CoV）和中东呼吸综合征冠状病毒（MERS - CoV），进一步证实了土贝母苷的抗病毒活性和NPC1的功能。因此，NPC1是高致病性人类冠状病毒（HCoV）在晚期内体中关键的进入辅助因子，土贝母苷有望成为针对这些人类冠状病毒和丝状病毒的一种新的应对措施。
新冠病毒如何进入细胞并引发新冠肺炎仍在深入研究中。在此，作者发现了人类冠状病毒和丝状病毒进入之间意想不到的相互作用，并发现了针对这些高致病性病毒的泛抑制剂。
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. How SARS-CoV-2 enters cells and causes COVID-19 is still under intensive investigation. Here, the authors identify unexpected crosstalk between human coronavirus and filovirus entry and discover pan-inhibitors for these highly pathogenic viruses.
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影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
64.5
作者：
Daniloski Z;Jordan TX;Wessels HH;Hoagland DA;Kasela S;Legut M;Maniatis S;Mimitou EP;Lu L;Geller E;Danziger O;Rosenberg BR;Phatnani H;Smibert P;Lappalainen T;tenOever BR;Sanjana NE
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影响因子：
11.4
作者：
Miller, Emily Happy;Obernosterer, Gregor;Chandran, Kartik
通讯作者：
Chandran, Kartik
影响因子：
6.4
作者：
Basu, Arnab;Mills, Debra M.;Bowlin, Terry L.
通讯作者：
Bowlin, Terry L.
影响因子：
5.8
作者：
Mirdita, Milot;Steinegger, Martin;Soeding, Johannes
通讯作者：
Soeding, Johannes