Dynamic Chirality in the Mechanism of Action of Allosteric CD36 Modulators of Macrophage-Driven Inflammation

Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp² 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.