8VRP

HIV-CA Disulfide linked Hexamer bound to 4-Quinazolinone Scaffold inhibitor

This is a non-PDB format compatible entry.

Summary for 8VRP

• Entry DOI: 10.2210/pdb8vrp/pdb
• Descriptor: Spacer peptide 1, N-[(1S)-1-[(3P,7M)-3-{4-chloro-3-[(ethanesulfonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl}-7-(3-fluoro-4-formylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl]acetamide, IODIDE ION, ... (4 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: 3
• Total formula weight: 79192.37

Authors

Goldstone, D.C.,Walsham, L. (deposition date: 2024-01-22, release date: 2025-07-23, Last modification date: 2026-08-12)

Primary citation

Zhang, X.,Sun, L.,Walsham, L.,Ma, Y.,Ding, D.,Wang, M.,Zhao, F.,Zhang, J.,Wang, Z.,Xu, S.,Jiang, X.,Zhou, Y.,De Clercq, E.,Pannecouque, C.,Chen, C.H.,Goldstone, D.C.,Liu, X.,Dick, A.,Zhan, P.
Discovery of 4-Quinazolinone-Containing Phenylalanine Derivatives as Potent, Resistant-Tolerant HIV Capsid Inhibitors.
MedComm (2020), 7:e70746-e70746, 2026

PubMed Abstract: The HIV-1 capsid (CA) is a validated antiviral target that plays critical roles in both the early and late stages of the viral life cycle. Using structure-based strategy, we designed and synthesized a series of phenylalanine derivatives containing a 4-quinazolinone scaffold as novel HIV-1 CA inhibitors. Among them, exhibited potent antiviral activity in MT-4 cells against HIV-1 NL4-3 (EC = 0.65 ± 0.27 nM) and effectively protected cells from HIV-1 IIIB infection. SPR revealed that interacts strongly with CA hexamers (  = 2.7 ± 0.5 nM) with an extended residence time and competes with host factors CPSF6 and NUP153, disrupting CA assembly and disassembly. retained activity against lenacapavir (LEN)-resistant strains, such as N74D (11-fold shift vs. 20-fold for LEN). Crystallographic analysis revealed that binds at the CA NTD-CTD interface and forms hydrogen bonds with Thr107 and Ser41 (NTD-NTD interface). Pharmacological evaluation demonstrated favorable properties, including good plasma stability, low toxicity (SI > 1571), and suitable pharmacokinetics with a prolonged half-life following subcutaneous administration (  = 19.9 h). Overall, this study identifies 4-quinazolinone-based phenylalanine derivatives as promising HIV-1 CA inhibitors and highlights as a potential long-acting therapeutic candidate for HIV-1 treatment.

PubMed: 42087906
DOI: 10.1002/mco2.70746

Experimental method

X-RAY DIFFRACTION (1.8 Å)