title: Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides.
abstract: Metastin/kisspeptin, a 54-amino acid peptide, is the ligand of the G-protein-coupled receptor KISS1R which plays a key role in pathways that regulate reproduction and cell migration in many endocrine and gonadal tissues. The N-terminally truncated decapeptide, metastin(45-54), has 3-10 times higher receptor affinity and intracellular calcium ion-mobilizing activity but is rapidly inactivated in serum. In this study we designed and synthesized stable KISS1R agonistic decapeptide analogs with selected substitutions at positions 47, 50, and 51. Replacement of glycine with azaglycine (azaGly) in which the α-carbon is replaced with a nitrogen atom at position 51 improved the stability of amide bonds between Phe(50)-Gly(51) and Gly(51)-Leu(52) as determined by in vitro mouse serum stability studies. Substitution for tryptophan at position 47 with other amino acids such as serine, threonine, β-(3-pyridyl)alanine, and D-tryptophan (D-Trp), produced analogs that were highly stable in mouse serum. D-Trp(47) analog 13 showed not only high metabolic stability but also excellent KISS1R agonistic activity. Other labile peptides may have increased serum stability using amino acid substitution.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa, Japan. taiji.asami@takeda.com
authors.forename: Taiji
authors.initials: T
authors.lastname: Asami
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishizawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nishibori
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
authors.forename: Chieko
authors.initials: C
authors.lastname: Kitada
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D005998:Glycine / Q000031:analogs & derivatives; D006801:Humans; D059648:Kisspeptins / Q000097:blood* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D044967:Serum / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000596:Amino Acids; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C012787:3-pyridylalanine; D014364:Tryptophan; D000409:Alanine; D005998:Glycine