8TQP

HIV-CA Disulfide linked Hexamer bound to Quinazolin-4-one Scaffold inhibitor

8TQP の概要

• エントリーDOI: 10.2210/pdb8tqp/pdb
• 関連するPDBエントリー: 8TOV
• 分子名称: Gag polyprotein, 2-[4-(4-aminobenzene-1-sulfonyl)-2-oxopiperazin-1-yl]-N-{(1R)-2-(3,5-difluorophenyl)-1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}acetamide (3 entities in total)
• 機能のキーワード: hiv-1, human immunodeficiency virus, capsid, hiv-ca, capsid inhibitor, hiv restriction, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 313967.98

構造登録者

Goldstone, D.C.,Barnett, M.J.,Taka, J.R.H. (登録日: 2023-08-08, 公開日: 2023-12-20, 最終更新日: 2024-11-06)

主引用文献

Xu, S.,Sun, L.,Barnett, M.,Zhang, X.,Ding, D.,Gattu, A.,Shi, D.,Taka, J.R.H.,Shen, W.,Jiang, X.,Cocklin, S.,De Clercq, E.,Pannecouque, C.,Goldstone, D.C.,Liu, X.,Dick, A.,Zhan, P.
Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators.
J.Med.Chem., 66:16303-16329, 2023

PubMed Abstract: Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives and showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of and in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, and significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of in human liver microsomes compared to controls. Overall, and highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

PubMed: 38054267
DOI: 10.1021/acs.jmedchem.3c01647

実験手法

X-RAY DIFFRACTION (2.9 Å)