Structural Basis of Second-Generation HIV-1 Maturation Inhibitor Activity by Magic Angle Spinning NMR

The CA-SP1 junction of HIV-1 Gag forms a six-helix bundle (6HB) within the immature Gag lattice, sequestering the CA-SP1 cleavage site. Maturation inhibitors (MIs), such as Bevirimat (BVM) and its analogs, are an emerging class of HIV-1 antiviral compounds that stabilize Gag maturation intermediates by interfering with CA-SP1 proteolytic processing. Here, we report the binding modes of a potent second-generation BVM analog with an extended scaffold, HRF-4467, in crystalline CACTD-SP1-NC11 assemblies with inositol hexakisphosphate (IP6), as determined by magic-angle-spinning solid-state NMR (MAS NMR) spectroscopy. The atomic-level structure reveals that HRF-4467 binds asymmetrically in the SP1-NC11 six-helix bundle and stabilizes its helical conformation in the immature lattice, in both the wild-type and the BVM-resistant SP1-V7A Gag variant. Additionally, in the presence of HRF-4467, IP6 adopts distinct conformations in the wild-type CACTD-SP1-NC11 and the SP1-V7A variant. Taken together, our results establish a molecular basis for HRF-4467's improved antiviral activity relative to BVM and suggest strategies for designing inhibitors with enhanced performance against MI-resistant HIV-1 variants for potential therapeutic use.

Kumar, K., Zadorozhnyi, R., Porter, T. N., Martinez, J. A., Quinn, C. M., Ablan, S. D., Freed, E. O., Nitz, T. J., Wild, C. T., Ganser-Pornillos, B. K., Pornillos, O., Gronenborn, A. M., Polenova, T.

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