title: Sauvagine analogs selective for corticotropin releasing factor 2 receptor: effect of substitutions at positions 35 and 39 on CRF2R selectivity.
abstract: Corticotropin releasing factor 2 receptor selective analogs of the amphibian peptide sauvagine, a member of the corticotropin releasing factor (CRF) peptide family, have therapeutic potential for the treatment of skeletal muscle atrophy. Previously, we demonstrated that [P11X12X13]Svg peptides have improved CRF2R selectivity, although not to the level of CRF2R selective hormones such as urocortin 2 and urocortin 3. Since we also demonstrated a potential for improvement in selectivity of sauvagine by modifications of residues 35 and 39, we investigated substitutions of these amino acids in selected [P11X12X13]Svg peptides. We have observed that substitution of Arg35 in sauvagine to Ala35 (the amino acid found in all CRF2R selective agonists), increased the selectivity of [P11, X12, X13]Svg analogs. In contrast, substitution of Asp39 in sauvagine to Ala39 (also the amino acid found in all CRF2R selective agonists) did not further increase the selectivity of [P11, X12, X13, A35]Svg analogs. Thus, the residues 35 along with 11, 12, and 13 in sauvagine represent important sites for improving CRF2R selectivity.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA. amazur@cinci.rr.com
authors.forename: Adam W
authors.initials: AW
authors.lastname: Mazur
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Michelle
authors.initials: M
authors.lastname: Tscheiner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Donnelly
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Isfort
mesh_terms: D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D029845:Amphibian Proteins; D000818:Animals; D001216:Asparagine / Q000235:genetics; D001665:Binding Sites; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D036361:Peptide Hormones; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists*
chemical_list: D029845:Amphibian Proteins; C101531:CRF receptor type 2; D036361:Peptide Hormones; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D001216:Asparagine; C025727:sauvagine; D000409:Alanine