Structure-guided discovery of HIV-1 capsid inhibitors: From diverse binding sites to resistance-resilient antiviral strategies.

HIV-1 capsid (CA) protein is a key target for next-generation antiretrovirals, driving multiple stages of the viral life cycle. This review covers 2020-2026 advances in CA-targeted drug discovery: high-resolution CA structures; allosteric regulation by host metabolite IP6; medicinal chemistry optimization of PF74 derivatives via scaffold hopping and conformational restriction to enhance potency and metabolic stability; the development and clinical use of lenacapavir-the first ultra-long-acting CA inhibitor-and mechanisms of resistance (e.g., M66I); emerging inhibitors against resistant strains and cryptic binding sites; and current challenges. We also briefly discuss emerging approaches such as AI-driven design and PROTACs (Proteolysis-Targeting Chimeras), and highlight long-acting combination regimens as a promising path toward an HIV-1 functional cure.