Potent peptide agonists for human melanocortin 3 and 4 receptors derived from enzymatic cleavages of human β-MSH(5–22) by dipeptidyl peptidase I and dipeptidyl peptidase IV

Abstract

Human β-MSH(1–22) was first isolated from human pituitary as a 22-amino acid (aa) peptide derived from a precursor protein, pro-opiomelanocortin (POMC). However, Bertagna et al. demonstrated that a shorter human β-MSH(5–22), (DEGPYRMEHFRWGSPPKD), is a true endogenous peptide produced in human hypothalamus. In this report, we demonstrated that in vitro enzymatic cleavage of native human β-MSH(5–22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, generated two potent MC3/4R peptide analogues, β-MSH(7–22) (GPYRMEHFRWGSPPKD) and β-MSH(9–22) (YRMEHFRWGSPPKD). In fact, the MC4R binding affinity and functional potency of β-MSH(7–22) ( K i = 4.6 nM, EC50 = 0.6 nM) and β-MSH(9–22) ( K i = 5.7 nM, EC50 = 0.6 nM) are almost an order of magnitude greater than those of their parent peptide, β-MSH(5–22) (MC4R, K i = 23 nM, EC50 = 3 nM). Furthermore, the DPP-I/DPP-IV cleaved peptide, β-MSH(9–22), when administered intracerebroventricularly (ICV) at a dose of 3 nmol/rat, potently induced an acute negative energy balance in a diet-induced obese rat model, while its parent molecule, β-MSH(5–22), administered at the same dose did not have any effect. These data suggest that DPP-I and DPP-IV may play a role in converting the endogenous β-MSH(5–22) to more potent peptides that regulate energy homeostasis in the hypothalamus.