Diversity-Oriented A<sup>3</sup>-Macrocyclization for Studying Influences of Ring-Size and Shape of Cyclic Peptides: CD36 Receptor Modulators
Ragnhild G. Ohm, Mukandila Mulumba, Ramesh Chingle, Ahsanullah Ahsanullah, Jinqiang Zhang, Sylvain Chemtob, Huy Ong, William D. Lubell
Abstract
Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.