title: Trypsin resistance of a decapeptide KISS1R agonist containing an Nω-methylarginine substitution.
abstract: Metastin/kisspeptin is an amidated peptide with 54 amino acid residues isolated from human placental tissues as a ligand of the orphan G-protein-coupled receptor KISS1R that is expressed throughout the central nervous system and in a variety of endocrine and gonadal tissues. Compared to the full-length metastin protein, the N-terminal truncated peptide metastin(45-54) has 3-10 times higher receptor affinity and enhanced ability to increase intracellular calcium concentration which is essential for activation of protein kinases involved in intracellular signaling in a number of pathways that affect reproduction and cell migration. However, metastin(45-54) is rapidly inactivated in serum. In this study, we designed and synthesized a number of metastin(45-54) analogs and evaluated their agonistic activity and trypsin resistance. Among analogs with substitutions of arginine at position 53, N(ω)(-)methylarginine analog 8 showed 3-fold more potent agonistic activity compared with metastin(45-54). Furthermore, analog 8 was shown to resist trypsin cleavage between positions 53 and 54. This substitution may be useful in the development of other Arg-containing peptides for which the avoidance of cleavage is desired.
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: Yasuko
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
authors.forename: Chieko
authors.initials: C
authors.lastname: Kitada
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000031:analogs & derivatives*; D006801:Humans; D059648:Kisspeptins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000074502:Receptors, Kisspeptin-1; D014357:Trypsin / Q000378:metabolism*
chemical_list: C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D001120:Arginine; D014357:Trypsin