Modifications of the human urocortin 2 peptide that improve pharmacological properties.
Recently, we demonstrated that the corticotropin releasing factor 2 receptor agonist, urocortin 2, demonstrated anti-atrophy effects in rodent skeletal muscle atrophy models. Compared to other CRF2R agonists however, the in vivo pharmacological potency of urocortin 2 is poor when it is administered by continuous subcutaneous infusion. Therefore, we attempted to modify the structure of urocortin 2 to improve in vivo efficacy when administered by subcutaneous infusion. By substituting amino acid residues in the linker region of urocortin 2 (residues 22-32), we have demonstrated improved in vivo potency without altering selectivity, probably through reduced CRFBP binding. In addition, attempts to shorten urocortin 2 generally resulted in inactive peptides, demonstrating that the 38 amino acid urocortin 2 peptide is the minimal pharmacophore.
Isfort
Robert J
RJ
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA. isfort.rj@pg.com
Wang
Feng
F
Tscheiner
Michelle
M
Dolan
Elizabeth
E
Bauer
Mary Beth
MB
Lefever
Frank
F
Reichart
Deborah
D
Wehmeyer
Kenneth R
KR
Reilman
Raymond A
RA
Keck
Bradly D
BD
Hinkle
Richard T
RT
Mazur
Adam W
AW
D000595:Amino Acid Sequence; D000818:Animals; D001284:Atrophy; D002460:Cell Line; D045744:Cell Line, Tumor; D003346:Corticotropin-Releasing Hormone / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D054832:Urocortins
D010455:Peptides; C426705:UCN2 protein, human; D054832:Urocortins; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone