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.