Agouti-related protein: Conversion from a Melanocortin receptor antagonist to agonist

ORGN 218

Carrie Haskell-Luevano, carrie@cop.ufl.edu1, Arthur S. Edison2, Andrzej Wilczynski, andrzej@ufl.edu1, Krista R. Wilson1, Christine G. Joseph1, and Zhimin Xiang1. (1) Department of Medicinal Chemistry, University of Florida, P.O.Box 100485, Gainesville, FL 32610-0485, (2) Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 36211
The Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 receptors (MC3R, MC4R) and is involved in the regulation of satiety and energy homeostasis. This 132 amino acid protein consists of a C-terminal domain (87-132) containing five disulfide bridges that has been characterized as resulting in the same potency as the full length protein. Structure-activity studies of monocyclic, bicyclic, and chimeric AGRP-melanocortin agonist peptide templates has resulted in the conversion of the AGRP antagonist into a potent melanocortin receptor agonist. A combination of ligand SAR, 2D NMR, and computer GPCR homology molecular modeling studies has resulted in putative ligand-receptor interactions hypothesized to differentiate the antagonist versus agonist melanocortin receptor pharmacology.
 

Ralph F. Hirschmann Award in Peptide Chemistry
1:30 PM-5:00 PM, Monday, 27 March 2006 Georgia World Congress Center -- C303/304/305, Oral

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006