Conformations and mitochondrial uncoupling activity of synthetic emerimicin fragments

Abstract

Several amino terminal fragments of the emerimicins (Ac-Phe¹-Aib²-Aib³-Aib⁴-Val⁵-Gly⁶-Leu⁷-Aib⁸-Aib⁹-Hyp¹⁰-Gln¹¹-D-Iva¹²-Hyp¹³-Ala/Aib¹⁴-Phol¹⁵) ranging in length from five to ten residues have been synthesized. Nuclear magnetic resonance studies have been carried out on the 1-5, 6-10, 1-6, 1-7, 1-8, 1-9, and 1-10 fragments. The number of solvent-shielded NH groups in CDCl₃ solutions for 1-5, 1-6, 1-7, 1-8, 1-9, and 1-10 indicate that 3₁₀-helical structures are favored in this solvent. In (CD₃)₂SO, an additional NH group, assigned to Aib(3) NH is solvent exposed in the fragments longer than six residues, suggesting partial unfolding of the N-terminal β-turn or transition to an α-helical conformation. The data for fragment 6-10 are consistent with a conformation having a single Leu-Aib β-turn. Infrared studies suggest an increase in the number of intramolecular hydrogen bonds with increasing peptide chain length. Appreciable mitochondrial uncoupling activity is observed for peptides with a chain length of at least seven residues. The order of efficiencies of the fragments is 1-7 < 1-8 ~ 1-10 < 1-9, with the decapeptide exhibiting anomalously low uncoupling activity.