Dept. of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, India.
School of Chemistry, University of Hyderabad, Hyderabad 500046, India.
Bioorg Med Chem. 2021 Dec 15;52:116526. doi: 10.1016/j.bmc.2021.116526. Epub 2021 Nov 20.
The HIV-1 invasion is initiated with the interaction of viral glycoprotein gp120 and cellular receptor CD4. The binding mechanism reveals two major hotspots involved in gp120-CD4 interaction. The first one is a hydrophobic cavity (Phe43 cavity) on gp120 capped with phenyl ring of phe43 and the second is the electrostatic interaction between positive charge of Arg59 and negative charge of Asp368. Targeting these hotspots, small molecules for entry inhibition and HIV-1 neutralization were designed and tested. In the process, pyrimidine derivatives were identified as potent molecules to intercept gp120-CD4 binding by targeting both the hotspots. Herein, the synthesis, characterization of 1,2,3,4-Tetrahydropyrimidine derivatives, and biological evaluation on 93IN101, a clade C virus are presented. The paper presents a novel set of entry inhibitors to target dual hotspots on gp120 to inhibit protein-protein interactions.
HIV-1 的入侵是由病毒糖蛋白 gp120 与细胞受体 CD4 的相互作用引发的。结合机制揭示了 gp120-CD4 相互作用涉及的两个主要热点。第一个热点是 gp120 上带有苯环的 Phe43 封盖的疏水性腔（phe43 腔），第二个热点是 Arg59 的正电荷与 Asp368 的负电荷之间的静电相互作用。针对这些热点，设计并测试了用于进入抑制和 HIV-1 中和的小分子。在此过程中，嘧啶衍生物被鉴定为通过针对两个热点来拦截 gp120-CD4 结合的有效分子。本文介绍了一系列新型 1,2,3,4-四氢嘧啶衍生物的合成、表征以及对 93IN101（一种 C 型病毒）的生物学评估。该论文提出了一组新的进入抑制剂，以针对 gp120 上的两个热点来抑制蛋白质-蛋白质相互作用。
