Sauvagine analogs selective for corticotropin releasing factor 2 receptor: effect of substitutions at positions 35 and 39 on CRF2R selectivity

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.