Targeting the transmembrane domain 5 of latent membrane protein 1 using small molecule modulators

文献类型： 外文期刊

第一作者： Zhang, Bo

作者： Zhang, Bo;Wang, Yibo;Lin, Cong;Li, Hongyuan;Wang, Xiaojie;Wang, Hongshuang;Wang, Xiaohui;Zhang, Bo;Wang, Xiaohui;Peng, Yinghua;Mineev, Konstatin S.;Mineev, Konstatin S.;Wilson, Andrew J.;Wilson, Andrew J.

作者机构：

关键词： Protein-protein interactions; Pentamidine analogues; Latent membrane protein 1; The fifth transmembrane domain (TMD-5); Epstein-barr virus; Small molecule modulators

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：5.572； 五年影响因子：5.207 ）

ISSN： 0223-5234

年卷期： 2021 年 214 卷

页码：

收录情况： SCI

摘要： Protein-protein interactions (PPIs) play a critical role in living cells and represent promising targets for the drug discovery and life sciences communities. However, lateral transmembrane PPIs are difficult targets for small-molecule inhibitor development given less structural information is known and fewer ligand discovery methods have been explored compared to soluble proteins. In this study, the interactions of the transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) were disrupted by pentamidine derivatives to curb the committed step of EBV infection. A pentamidine derivative 2 with a 7-atom di-amide linker had the best activity whilst switching the amide regiochemistry in the linker influenced membrane permeability and abolished anti TMD-5 activity. Molecular dynamics simulations were performed to understand the interaction between pentamidine derivatives and TMD-5, and to rationalise the observed structure-activity relationships. This study explicitly demonstrated that the interaction of small molecule with lipid should be considered alongside interaction with the protein target when designing small molecules targeting the PPIs of TMDs. In all, this study provides proof of concept for the rational design of small molecules targeting transmembrane PPIs. (C) 2021 Elsevier Masson SAS. All rights reserved.

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