Targeting the transmembrane domain 5 of latent membrane protein 1 using small molecule modulators
Targeting the transmembrane domain 5 of latent membrane protein 1 using small molecule modulators
复制标题
使用小分子调节剂靶向潜在膜蛋白 1 的跨膜结构域 5
DOI：
10.1016/j.ejmech.2021.113210
复制
发表时间：
2021-02-04
影响因子：
6.7
通讯作者：
Wang，Xiaohui
中科院分区：
文献类型：
--
作者：
Zhang，Bo;Wang，Yibo;Wang，Xiaohui
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 derivative2with 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.
