Potent peptide agonists for human melanocortin 3 and 4 receptors derived from enzymatic cleavages of human beta-MSH(5-22) by dipeptidyl peptidase I and dipeptidyl peptidase IV.
Human beta-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 beta-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 beta-MSH(5-22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, generated two potent MC3/4R peptide analogues, beta-MSH(7-22) (GPYRMEHFRWGSPPKD) and beta-MSH(9-22) (YRMEHFRWGSPPKD). In fact, the MC4R binding affinity and functional potency of beta-MSH(7-22) (Ki=4.6 nM, EC50=0.6 nM) and beta-MSH(9-22) (Ki=5.7 nM, EC50=0.6 nM) are almost an order of magnitude greater than those of their parent peptide, beta-MSH(5-22) (MC4R, Ki=23 nM, EC50= 3nM). Furthermore, the DPP-I/DPP-IV cleaved peptide, beta-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, beta-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 beta-MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus.
Division of Endocrine Research, DC0424 Lilly Corporate Center, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285, USA. hsiung@Lilly.com
Hansen M
HM
Hsiung
David L
DL
Smiley
Xing-yue
XY
Zhang
Lianshan
L
Zhang
Liang Zeng
LZ
Yan
Libbey
L
Craft
Mark L
ML
Heiman
Dennis P
DP
Smith
D000818:Animals; D020789:Cathepsin C / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000502:physiology; D008297:Male; D010455:Peptides / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D019824:beta-MSH / Q000378:metabolism*
D010455:Peptides; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH; D020789:Cathepsin C; D018819:Dipeptidyl Peptidase 4