Targeted Degradation of Capsid by Host-Hijacking PROTAC Overcomes Drug Resistance.

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 IIA-4 with VHL E3 ligase ligand. Among these, VHL-3 exhibited potent anti-HIV-1 activity in MT-4 cells (EC50 = 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, DC50 = 812 nM; late stage, DC50 = 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.