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

HRF-4467 binds asymmetrically to the SP1-NC11 six-helix bundle in crystalline CACTD-SP1-NC11 assemblies, stabilizing helical conformation in both wild-type and SP1-V7A.

• Why it matters: Second-generation maturation inhibitors aim to block CA-SP1 proteolytic processing, but resistance can emerge; a molecular binding picture is needed to guide improved inhibitor design.
• What they did: Using magic-angle-spinning solid-state NMR, the authors determined HRF-4467 binding modes in CACTD-SP1-NC11 crystals with IP6, including the BVM-resistant SP1-V7A variant.
• The result: HRF-4467 stabilizes immature-lattice helicity and alters IP6 conformations differently in wild-type versus SP1-V7A, providing a basis for designing inhibitors with better activity against MI-resistant variants.

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