8TOV

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

Summary for 8TOV

• Entry DOI: 10.2210/pdb8tov/pdb
• Descriptor: Matrix protein p17, 2-[4-(4-aminobenzene-1-sulfonyl)-2-oxopiperazin-1-yl]-N-[(1R)-2-(3,5-difluorophenyl)-1-{3-[4-(morpholine-4-sulfonyl)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl]acetamide (3 entities in total)
• Functional Keywords: hiv-1, human immunodeficiency virus, capsid, hiv-ca, capsid inhibitor, hiv restriction, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 12
• Total formula weight: 315397.68

Authors

Goldstone, D.C.,Barnett, M.J.,Taka, J.R.H. (deposition date: 2023-08-04, release date: 2023-12-20, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)