J. Med. Chem. 62 (24) 11071-11079 [2019-12-26; online 2019-12-13]
Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp 2 and sp3 hybridization, resulting in stereodynamic interconversions of pseudo-R and -S-configurations by means of a planar intermediate. Cyclic azapeptides have shown unprecedented binding affinity to the cluster of differentiation 36 receptor (CD36) and ability to mitigate macrophage-driven inflammation by modulation of the toll-like receptor 2/6 pathway. A novel approach to synthesize cyclic peptides via A3-macrocyclization has been used to make R- and S-configuration controls to study the relevance of semicarbazide hybridization for modulator activity. Nuclear magnetic resonance spectroscopy analysis of potent cyclic azapeptide CD36 modulators (e.g., 1 and 2) and related cyclic peptides demonstrated that binding affinity correlated with conformational rigidity, and a hybridization preference for sp2 > S- > R-sp3 semicarbazide nitrogen configuration was evaluated. Evidence of the active conformation and the relevance for dynamic chirality serve as insights for creating cyclic (aza)peptide CD36 modulators to curb inflammation.