Synthesis of ¹⁵ N‐Labeled Bevirimat Derivatives as Isotopic Chemical Probes of HIV‐1 Maturation Inhibition

ABSTRACT Characterizing protein–drug interactions at the atomic level is challenging partly because small molecules can be difficult to detect within large biomolecular complexes. We have developed a strategy to introduce NMR‐active isotopic 15 N labels into derivatives of bevirimat (BVM), a triterpenoid inhibitor of HIV‐1 maturation. Isotopically labeled compounds were synthesized through concise and efficient routes using commercially available, isotopically enriched building blocks. Three 15 N‐labeled BVM derivatives were prepared to be used as molecular probes to investigate HIV‐1 protein interactions. These labeled compounds enable site‐specific 15 N detection of the inhibitor in both solution and solid‐state NMR experiments, which will be useful to obtain molecular‐level insight into the interactions between BVM derivatives and its target HIV‐1 Gag protein. Synthetic incorporation of NMR‐active isotopes produces chemical probes for atomic‐level analysis of next‐generation HIV‐1 therapeutics derived from BVM and can be applied to other derivatives of betulinic acid with various medical applications.