A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function

Chemical synthesis of Agouti proteins - Agouti and Agouti-related proteins - is complicated by their large size and by multiple cysteine residues located in the carboxyl terminal regions. Three human Agouti-related protein (AGRP) fragments, two of which correspond to a proposed endoprotease cleavage site between amino acids 82 and 83, mere synthesized and tested for anti-melanotropic activity using Xenopus laevis dermal melanophores, Amino-terminal fragments AGRP(25-51) and (54-82) were devoid of significant antagonist activity, whereas the amidated carboxyl-terminal AGRP fragment (83-132)-NH2 was potently active with an inhibitory equilibrium dissociation constant (K-i) of 0.7 nM, The ability to synthesize functionally active AGRP should help unravel its role in the central nervous system and its unusual properties with respect to interaction with the melanocortin family of G-protein coupled receptors. (C) 1998 Federation of European Biochemical Societies.