9N0V

Crystal structure of the HIV capsid hexamer bound to the small molecule long-acting inhibitor, KFA-027

This is a non-PDB format compatible entry.

Summary for 9N0V

• Entry DOI: 10.2210/pdb9n0v/pdb
• Descriptor: Capsid protein p24, N-[(1S)-1-{(3M)-3-[4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-[3-(methanesulfonyl)-3-methylbut-1-yn-1-yl]pyridin-2-yl}-2-phenylethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide (2 entities in total)
• Functional Keywords: hiv capsid hexamer, capsid inhibitor, long-acting inhibitor, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 4
• Total formula weight: 101273.13

Authors

Dinh, T.T.,Kvaratskhelia, M. (deposition date: 2025-01-24, release date: 2025-06-18, Last modification date: 2025-11-05)

Primary citation

Adu-Ampratwum, D.,Annamalai, A.S.,Dinh, T.,Lockwood, J.R.,Bockbrader, R.H.,Haney, R.,Kvaratskhelia, M.,Fuchs, J.R.
Delineating Structural Functionalities of Lenacapavir Amenable to Modifications for Targeting Emerging Drug-Resistant HIV‐1 Capsid Variants.
Acs Med.Chem.Lett., 16:2007-2014, 2025

PubMed 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 (EC ∼ 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.

PubMed: 41089487
DOI: 10.1021/acsmedchemlett.5c00405

Experimental method

X-RAY DIFFRACTION (2.98 Å)