Lenacapavir

Ma C, et al. Acta Pharmaceutica Sinica B, 2024, 14(12), 5512-5514.

Lenacapavir, a first-in-class HIV-1 capsid inhibitor, demonstrates remarkable efficacy in treating multidrug-resistant HIV-1 infections through its unique mechanism of targeting the capsid protein (p24). In the phase II/III CAPELLA trial (NCT04150068), lenacapavir was administered subcutaneously to adults with treatment-experienced, multidrug-resistant HIV-1. Participants received a 927 mg subcutaneous loading dose on day 1, followed by 927 mg maintenance doses every six months. Viral load was quantified using real-time PCR-based HIV-1 RNA assays, and over 80% of patients achieved <50 copies/mL at week 26. Structural insights were gained through X-ray crystallography (PDB: 6V2F, 6VKV), revealing lenacapavir's interactions with CA hexamers, stabilizing the capsid via hydrophobic and hydrogen-bonding networks. Furthermore, phase I pharmacokinetic studies in healthy volunteers demonstrated a slow-release profile with a half-life of 32-45 days, confirmed via LC-MS/MS plasma concentration analysis. This extended exposure surpasses the EC50 by over 24 weeks, supporting twice-yearly administration.

Patel P. C, et al. Trends in Pharmacological Sciences, 2023, 44(8), 553-554.

Lenacapavir, demonstrates a novel mechanism against HIV-1 by targeting the viral capsid protein rather than reverse transcriptase or integrase enzymes. In experimental studies, lenacapavir was applied in in vitro capsid assembly assays to assess its impact on viral morphogenesis. The compound binds at a conserved interface between capsid hexamers, as verified by X-ray crystallography and cryo-electron microscopy, disrupting both early and late stages of the viral life cycle.
To evaluate nuclear import inhibition, fluorescently labeled viral cDNA and confocal microscopy were employed in HeLa-derived cell lines to monitor the interaction of HIV-1 cores with host proteins Nup153 and CPSF6. Lenacapavir-treated samples showed diminished nuclear localization and reduced proviral DNA integration, confirmed by quantitative PCR. In capsid assembly experiments, the drug induced dose-dependent polymerization of recombinant capsid monomers, resulting in malformed, non-infectious structures.Resistance profiling via site-directed mutagenesis identified capsid mutations (e.g., M66I, Q67H) that reduced drug sensitivity. These findings reinforce lenacapavir's efficacy and mutation-resilient profile.