Delineating Structural Functionalities of Lenacapavir Amenable to Modifications for Targeting Emerging Drug-Resistant HIV‑1 Capsid Variants

  • ACS Med Chem Lett. 2025 Sep 23;16(10):2007-2014. doi: 10.1021/acsmedchemlett.5c00405.
Daniel Adu-Ampratwum  1 ,  Arun S Annamalai  2 ,  Tung Dinh  2 ,  Jeffrey R Lockwood  1 ,  Ross H Bockbrader  1 ,  Reed Haney  2 ,  Mamuka Kvaratskhelia  2 ,  James R Fuchs  1  2
Affiliations
  • 1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 2. Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado 80045, United States.
PMID: 41089487 DOI: 10.1021/acsmedchemlett.5c00405
Abstract

Lenacapavir (LEN) is a new, first-in-class, long acting, HIV-1 capsid (CA)-targeting inhibitor for treating multidrug-resistant HIV-1 infections. LEN exhibits high potency against all major HIV-1 subtypes including variants resistant to current antiretroviral therapies providing a life-saving opportunity for heavily treatment-experienced adults with multidrug-resistant HIV-1. Despite this, LEN has a relatively low barrier to viral resistance. Clinical trials identified resistance-associated mutations near LEN binding site, with the M66I variant exhibiting highest level of resistance (>3200-fold). These findings necessitate continuing efforts to develop next-generation inhibitors against emerging LEN-resistant mutation. We focused on identifying LEN structural functionalities amenable to modifications and to develop LEN analogs with improved Antiviral activity against the M66I mutant. Here, we report a new LEN analog, KFA-027, with substantially improved Antiviral activity (EC50 ∼ 444 nM, >20-fold) against M66I variant. Overall, these findings suggest a route for developing next-generation LEN analogs against WT and emerging drug-resistant CA mutations.

Keywords
GS-6207; HIV-1; Lenacapavir (LEN); antiretroviral therapy; capsid; drug-resistant mutations; first-in-class; inhibitor; long-acting; resistance-associated-mutations (RAMs); structure−activity relationship (SAR) study.
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