Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism.
Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism.
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DOI：
10.1016/j.csbj.2023.01.014
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发表时间：
2023
影响因子：
6
通讯作者：
Batista, Victor S.
中科院分区：
文献类型：
--
作者：
Maschietto, Federica;Qiu, Tianyin;Wang, Jimin;Shi, Yuanjun;Allen, Brandon;Lisi, George P.;Lolis, Elias;Batista, Victor S.
关键词：
SARS-CoV-2刺突三聚体的受体结合结构域（RBD）表现出“上”和“下”构象，通常被中和抗体靶向。只有在“向上”构型中，RBD才能与宿主细胞的ACE 2受体结合并启动病毒增殖过程。在这里，我们确定了一种先导化合物（3-氧代-丙戊酸-辅酶A缀合物或Val-CoA），其稳定了RBD处于向下构象的尖峰三聚体。Val-CoA与三个R408残基相互作用，每个RBD一个残基，这显著地将亚基间R408-R408距离减少了1013 μ m，并关闭了由三个RBD形成的中心孔。实验证据表明，R408是一个触发机制的一部分，控制的穗三聚体的融合前到融合后的状态转换。通过使RBD稳定在向下构型，这种化合物和其他相关化合物可能会减弱病毒传播。Val-CoA与刺突三聚体结合的研究结果表明，设计变构抗病毒药物的新方法不必竞争特定的病毒-受体相互作用，而是阻碍与宿主细胞相互作用所必需的病毒膜蛋白的构象运动。在这里，我们介绍了一种方法，以确定稳定的RBD在三聚体的“向下”配置的先导化合物，以靶向刺突蛋白。当这些化合物将单体RBD免疫原三聚为共免疫原时，它们还可以诱导新型的非ACE 2阻断抗体，这些抗体可以阻止病毒的局部细胞间传播，为抑制SARS-CoV-2提供了一种新方法。MD衍生的ESP图谱显示，三个R408残基与丙戊酸盐-CoA结合物在其中心孔处形成π-π-π堆积和多重氢键相互作用。该化合物的结合使尖峰三聚体处于闭合状态。VPA-CoA结合SARS-CoV-2的刺突三聚体的三个RBD的闭合形式。R408是刺突三聚体的开闭动力学的触发机制的一部分VPA-CoA的结合通过氢键增强亚基间RBD相互作用VPA-CoA靶向刺突三聚体的未探索的变构调节位点VPA-CoA和用于下一代刺突疫苗的相关化合物
The receptor-binding domains (RBDs) of the SARS-CoV-2 spike trimer exhibit "up" and "down" conformations often targeted by neutralizing antibodies. Only in the “up” configuration can RBDs bind to the ACE2 receptor of the host cell and initiate the process of viral multiplication. Here, we identify a lead compound (3-oxo-valproate-coenzyme A conjugate or Val-CoA) that stabilizes the spike trimer with RBDs in the down conformation. Val-CoA interacts with three R408 residues, one from each RBD, which significantly reduces the inter-subunit R408-R408 distance by ∼ 13 Å and closes the central pore formed by the three RBDs. Experimental evidence is presented that R408 is part of a triggering mechanism that controls the prefusion to postfusion state transition of the spike trimer. By stabilizing the RBDs in the down configuration, this and other related compounds can likely attenuate viral transmission. The reported findings for binding of Val-CoA to the spike trimer suggest a new approach for the design of allosteric antiviral drugs that do not have to compete for specific virus-receptor interactions but instead hinder the conformational motion of viral membrane proteins essential for interaction with the host cell. Here, we introduce an approach to target the spike protein by identifying lead compounds that stabilize the RBDs in the trimeric “down” configuration. When these compounds trimerize monomeric RBD immunogens as co-immunogens, they could also induce new types of non-ACE2 blocking antibodies that prevent local cell-to-cell transmission of the virus, providing a novel approach for inhibition of SARS-CoV-2. MD-derived ESP maps reveal that three R408 residues make π-π-π stacking and multiple H-bonding interactions with Valproate-CoA conjugate bound at its central pore. The binding of this compound populates the spike trimer in a closed state. VPA-CoA binds the closed form of three RBDs of the spike trimer of SARS-CoV-2. R408 is part of a triggering mechanism for open-closing dynamics of the spike trimer Binding of VPA-CoA enhances inter-subunit RBD interactions via hydrogen bonds VPA-CoA targets an unexplored allosteric regulation site of the spike trimer VPA-CoA and related compounds for next generation of spike vaccines
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超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
影响因子：
18.2
作者：
Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
通讯作者：
Amaro RE
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.6
作者：
LEE, B;RICHARDS, FM
通讯作者：
RICHARDS, FM
影响因子：
64.8
作者：
Ke, Zunlong;Oton, Joaquin;Briggs, John A. G.
通讯作者：
Briggs, John A. G.
影响因子：
64.8
作者：
CHOTHIA, C;JANIN, J
通讯作者：
JANIN, J