Beta-Amino Acid Analogs of an Insect Neuropeptide Feature Potent Bioactivity and Resistance to Peptidase Hydrolysis

摘要

Insect neuropeptides of the insect kinin class share a common C- terminal pentapeptide sequence F(sup1)X(sup 2 sub 1) X(sup 3 sub 2) W(sup 4)G(sup 5)-NH2 (X(sup 3 sub 2) = P, S, A) and regulate such critical physiological processes as water balance and digestive enzyme release. Analogs of the insect kinin class, in which the critical residues of F1, P3, and W4 were replaced with beta3-amino acid or their b2-homo-amino acid variants, have been synthesized by the solid phase peptide strategy. The resulting single- and doublereplacement analogs were evaluated in an insect diuretic assay and enzyme digestion trials. Analogs modified in the core P3 position produce a potent and efficacious diuretic response that is not significantly different from that obtained with the endogenous achetakinin peptides. The analogs also demonstrate enhanced resistance to hydrolysis by ACE and NEP, endopeptidases that inactivate the natural insect neuropeptides. This paper describes the first instance of b-amino acids analogs of an arthropod peptide that demonstrate significant bioactivity and resistance to peptidase degradation.