Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry.
Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry.
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DOI：
10.1021/acsinfecdis.1c00658
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发表时间：
2022-10-14
影响因子：
5.3
通讯作者：
Herschhorn A
中科院分区：
文献类型：
--
作者：
Ratnapriya S;Braun AR;Cervera Benet H;Carlson D;Ding S;Paulson CN;Mishra N;Sachs JN;Aldrich CC;Finzi A;Herschhorn A
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）进入宿主细胞需要病毒刺突蛋白与血管紧张素转换酶2 （ACE2）受体结合，这引发随后的构象变化，以促进病毒和细胞在质膜或内吞作用下的融合。在这里，我们通过实验确定了具有三环（或类似）结构的选择性和广泛性SARS-CoV-2进入抑制剂。抑制作用仅限于感染的早期阶段，进入抑制剂与SARS-CoV-2刺突的受体结合域相互作用，但对受体（ACE2）的结合没有显著干扰。相反，这些化合物中的一些会诱导构象变化或影响刺突组装，并阻断SARS-CoV-2刺突细胞-细胞融合活性。广泛的抑制剂定义了一个高度保守的结合袋，该结合袋存在于SARS-CoV-1、SARS-CoV-2和所有测试的循环SARS-CoV-2变体的刺突上，并阻断介导病毒进入所需的SARS-CoV刺突活性。这些化合物为SARS-CoV-2尖峰地形以及进入途径的关键步骤提供了新的见解，并可作为开发针对sars - cov的广谱进入抑制剂的主要候选药物。摘要：三环抑制剂（如氨基苯妥品）可阻断SARS-CoV-2进入靶细胞。
Entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells requires binding of the viral spike protein to the angiotensin converting enzyme 2 (ACE2) receptor, which triggers subsequent conformational changes to facilitate viral and cellular fusion at the plasma membrane or following endocytosis. Here, we experimentally identified selective and broad inhibitors of SARS-CoV-2 entry that share a tricyclic ring (or similar) structure. Inhibitory effect was restricted to early steps during infection and the entry inhibitors interacted with the receptor binding domain of SARS-CoV-2 spike but did not significantly interfere with receptor (ACE2) binding. Instead, some of these compounds induced conformational changes or affected spike assembly and blocked SARS-CoV-2 spike cell-cell fusion activity. The broad inhibitors define a highly conserved binding pocket that is present on the spikes of SARS-CoV-1, SARS-CoV-2, and all circulating SARS-CoV-2 variants tested, and block SARS-CoV spike activity required for mediating viral entry. These compounds provide new insights into the SARS-CoV-2 spiks topography as well as into critical steps on the entry pathway, and can serve as lead candidates for the development of broad-range entry inhibitors against SARS-CoVs. Synopsis: Tricyclic ring inhibitors (e.g., aminobenztropine) block SARS-CoV-2 entry into target cells.
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影响因子：
--
作者：
Gruber SJ;Cornea RL;Li J;Peterson KC;Schaaf TM;Gillispie GD;Dahl R;Zsebo KM;Robia SL;Thomas DD
通讯作者：
Thomas DD
影响因子：
30.3
作者：
Case, James Brett;Rothlauf, Paul W.;Whelan, Sean P. J.
通讯作者：
Whelan, Sean P. J.
DOI：
10.1177/2472555217706478
发表时间：
2017-09
期刊：
SLAS discovery : advancing life sciences R & D
影响因子：
--
作者：
Lo CH;Vunnam N;Lewis AK;Chiu TL;Brummel BE;Schaaf TM;Grant BD;Bawaskar P;Thomas DD;Sachs JN
通讯作者：
Sachs JN
影响因子：
8.8
作者：
Harris, Miranda;Ratnapriya, Sneha;Herschhorn, Alon
通讯作者：
Herschhorn, Alon
影响因子：
4.4
作者：
Herschhorn, Alon;Marasco, Wayne A.;Hizi, Amnon
通讯作者：
Hizi, Amnon