title: G-CSF receptor-binding cyclic peptides designed with artificial amino-acid linkers.
abstract: Designing small molecules that mimic the receptor-binding local surface structure of large proteins such as cytokines or growth factors is fascinating and challenging. In this study, we designed cyclic peptides that reproduce the receptor-binding loop structures of G-CSF. We found it is important to select a suitable linker to join two or more discontinuous sequences and both termini of the peptide corresponding to the receptor-binding loop. Structural simulations based on the crystallographic structure of KW-2228, a stable and potent analog of human G-CSF, led us to choose 4-aminobenzoic acid (Abz) as a part of the linker. A combination of 4-Abz with beta-alanine or glycine, and disulfide bridges between cysteins or homocysteins, gave a structure suitable for receptor binding. In this structure, the side-chains of several amino acids important for the interactions with the receptor are protruding from one side of the peptide ring. This artificial peptide showed G-CSF antagonistic activity in a cell proliferation assay.
authors.affiliation: BioFrontier Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6, Asahi-machi, Machida-shi, Tokyo 194-8533, Japan. kshibata@kyowa.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Shibata
authors.forename: Kumiko
authors.initials: K
authors.lastname: Maruyama-Takahashi
authors.forename: Motoo
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hirayama
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry*; D006710:Homocysteine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry*; D015091:beta-Alanine / Q000737:chemistry
chemical_list: D000596:Amino Acids; D004220:Disulfides; D008024:Ligands; D010456:Peptides, Cyclic; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D006710:Homocysteine; D015091:beta-Alanine; D016179:Granulocyte Colony-Stimulating Factor; C072115:nartograstim; D003545:Cysteine; D005998:Glycine; D010129:4-Aminobenzoic Acid