The Aggregation Properties of Some Bradykinin Analogs

Abstract

Bradykinin (BK) is a peptide hormone with sequence Arg¹-Pro²-Pro³-Gly⁴-Phe⁵-Ser⁶-Pro⁷-Phe⁸-Arg⁹ and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. Bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to yield strong antagonists. Nuclear magnetic resonance studies have been carried out on many of these molecules with a view to determining their solution conformations. However, two such analogs, namely DArg-[Hyp³, Thi⁵, DSer⁶, DCpg⁷, Cpg⁸]-BK [I] and DArg-[Hyp³, DSer⁶, DCpg⁷, Cpg⁸]-BK [II] (Cpg = α-cyclopentyl-glycine; Hyp = 4-hydroxy-L-proline, Thi = β-(2-thienyl)-L-alanine), have exhibited an abnormal, non-linear temperature dependence for the amide NH proton of Cpg⁸. The NH of Arg⁹ also shows a slightly non-linear temperature dependence at higher temperatures above 25 °C. In addition, a very slow exchange rate for the NH protons of DCpg⁷, Cpg⁸ and Arg⁹ indicated aggregation of these two analogs, which was confirmed using the circular dichroism experiments.