26NL

Cryo-EM Structure of the HIV Capsid in Complex with VHL-3

This is a non-PDB format compatible entry.

Summary for 26NL

• Entry DOI: 10.2210/pdb26nl/pdb
• EMDB information: 80777
• Descriptor: Capsid protein p24, 2LZ-WFP-A1E9U-BAL-TBG-HYP, (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine (3 entities in total)
• Functional Keywords: hiv, capsid, inhibitor, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 12
• Total formula weight: 158980.91

Authors

Xue, L.,Gui, J. (deposition date: 2026-05-07, release date: 2026-07-22, Last modification date: 2026-09-16)

Primary citation

Wang, M.,Peng, Z.,Zhou, Y.,Ma, Y.,Gui, J.,Xu, S.,Jiang, X.,Tang, T.,Liu, X.,Pannecouque, C.,Xue, L.,Xiong, X.,Tang, K.,Wei, G.,Zhan, P.
Targeted Degradation of Capsid by Host-Hijacking PROTAC Overcomes Drug Resistance.
J.Med.Chem., 69:16878-16895, 2026

PubMed Abstract: The escalating prevalence of HIV-1 drug-resistant variants and the toxicity limitations of conventional antiretroviral therapies necessitate therapeutic strategies with novel mechanisms of action. This study focuses on HIV-1 capsid (CA), an essential replication-related viral protein. We developed CA-targeted proteolysis-targeting chimera (PROTAC) degraders by conjugating PF74-derived CA ligand with VHL E3 ligase ligand. Among these, - exhibited potent anti-HIV-1 activity in MT-4 cells (EC = 3.0 ± 1.5 nM), a 300-fold improvement over PF74. Mechanistic studies confirmed VHL-3 dose- and time-dependently reduced CA levels in HEK293T cells (early stage, DC = 812 nM; late stage, DC = 252 nM) via a proteasome-driven pathway. Notably, it effectively degraded clinically relevant CA-resistant mutants (N74D, K70R). This work pioneers the development of CA-targeted degraders, providing a framework for next-generation anti-HIV therapies with high potency and resistance barriers.

PubMed: 42438214
DOI: 10.1021/acs.jmedchem.6c00553

Experimental method

ELECTRON MICROSCOPY (2.8 Å)