Structural Basis for HIV-1 Maturation Inhibition by PF-46396 Determined by MAS NMR

Among the different types of HIV-1 maturation inhibitors, those that stabilize the junction between the capsid protein C-terminal domain (CA<sub>CTD</sub>) and the spacer peptide 1 (SP1) within the immature Gag lattice are promising candidates for antiretroviral therapies. Here, we report the atomic-resolution structure of CA<sub>CTD</sub>-SP1 assemblies with the small-molecule maturation inhibitor PF-46396 and the assembly cofactor inositol hexakisphosphate (IP6), determined by magic angle spinning (MAS) NMR spectroscopy. Our results reveal that although the two PF-46396 enantiomers exhibit distinct binding modes, they both possess similar anti-HIV potency. PF-46396 binding arrests IP6 dynamics in the six-helix bundle pore, and the two enantiomers induce unique IP6 orientations in the pore. Importantly, our data suggest the presence of monoanionic IP6 form in the complex. Our study establishes the structural basis for PF-46396 action and suggests a mechanistic model for drug resistance.

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Publication Details

Journal
Journal of the American Chemical Society
Published
2025-09-09
DOI
https://doi.org/10.1021/jacs.5c08455
Primary Topic
HIV Research and Treatment
Type
article
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article

Structural Basis for HIV-1 Maturation Inhibition by PF-46396 Determined by MAS NMR

Angela M. Gronenborn, Glenn P. A. Yap, Owen Pornillos, Barbie K. Ganser‐Pornillos et al.
1 links
Journal of the American Chemical Society
HIV Research and Treatment
article

Structural Basis for HIV-1 Maturation Inhibition by PF-46396 Determined by MAS NMR

Angela M. Gronenborn, Glenn P. A. Yap, Owen Pornillos, Barbie K. Ganser‐Pornillos, Brandon J. Kennedy, Sherimay D. Ablan, Eric O. Freed, Kaneil K. Zadrozny, Tatyana Polenova, Roman Zadorozhnyi, Caitlin M. Quinn, Christina M. Kraml, Daniel Sanner
article en

Abstract

Among the different types of HIV-1 maturation inhibitors, those that stabilize the junction between the capsid protein C-terminal domain (CA<sub>CTD</sub>) and the spacer peptide 1 (SP1) within the immature Gag lattice are promising candidates for antiretroviral therapies. Here, we report the atomic-resolution structure of CA<sub>CTD</sub>-SP1 assemblies with the small-molecule maturation inhibitor PF-46396 and the assembly cofactor inositol hexakisphosphate (IP6), determined by magic angle spinning (MAS) NMR spectroscopy. Our results reveal that although the two PF-46396 enantiomers exhibit distinct binding modes, they both possess similar anti-HIV potency. PF-46396 binding arrests IP6 dynamics in the six-helix bundle pore, and the two enantiomers induce unique IP6 orientations in the pore. Importantly, our data suggest the presence of monoanionic IP6 form in the complex. Our study establishes the structural basis for PF-46396 action and suggests a mechanistic model for drug resistance.

Journal of the American Chemical SocietyVol. 147(38)
University of Pittsburgh (US), Princeton University (US), University of Utah (US), Cancer Institute (WIA) (IN), IR Dynamics (United States) (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Lotus Clinical Research (US), Center for Cancer Research (US), University of Virginia (US), University of Delaware (US)
Openalex Percentile: Top 74%
HIV Research and Treatment
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