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 sp ² and sp ³ 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 A ³ -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 sp ² > S - > R -sp ³ 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.