Delineating structural functionalities of lenacapavir amenable to modifications for targeting emerging drug-resistant HIV-1 capsid variants.

Lenacapavir (LEN, Gilead Sciences) is a recently discovered, first-in-class, long acting, and ultra-potent HIV-1 capsid (CA)-targeting inhibitor for treatment of multi-drug-resistant HIV-1 infections. LEN exhibits high potency against all major HIV-1 types including the viral variants resistant to current antiretroviral therapies. Accordingly, LEN provides a lifesaving therapy for heavily treatment-experienced adults with multi-drug-resistant HIV-1. However, one notable shortcoming is a relatively low barrier of viral resistance to LEN. The clinical trials have identified resistance-associated mutations near the LEN binding site on HIV-1 CA including M66I, Q67H/K/N, K70R/H/N/S, N74D/H/K, A105S/T and T107N/A/C/S changes. Of these, the M66I variant exhibited the highest level of resistance (>3,200-fold) to LEN. These findings necessitate continuing medicinal chemistry efforts to develop next-generation HIV-1 CA inhibitors against the emerging LEN resistant mutation. Here, our SAR studies have focused on the identification of LEN structural functionalities amenable to modifications and the development of a LEN analog with improved antiviral activity against the M66I mutant virus. We report a new LEN analog, KFA-027, with substantially improved antiviral activity (EC50 of ~444 nM, >20-fold) against HIV-1(M66I CA) compared to the parent LEN. Overall, our findings suggest a route for the future development of improved analogs against WT and emerging drug-resistant CA mutations.