title: Discovery of a β-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology.
abstract: Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87-132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active β-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore. The most potent scaffold, c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], comprised the hexa-peptide β-hairpin loop from AGRP cyclized through a DPro-Pro motif. A 20 compound library was synthesized from this scaffold for further structure-activity relationship studies. The most potent peptide from this library was an asparagine to diaminopropionic acid substitution that possessed sub-nanomolar antagonist activity at the mMC4R and was greater than 160-fold selective for the mMC4R versus the mMC3R. The reported ligands may serve as probes to characterize the melanocortin receptors in vivo and leads in the development of novel therapeutics.
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Ericson
authors.affiliation: ‡Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wilczynski
authors.affiliation: ‡Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Sorensen
authors.affiliation: ‡Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.|‡Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D054369:Agouti-Related Protein / Q000737:chemistry*; D000818:Animals; D032701:Biomimetics; D000242:Cyclic AMP / Q000378:metabolism; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D054369:Agouti-Related Protein; D008024:Ligands; C574273:MC4R protein, mouse; D010446:Peptide Fragments; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP