title: Novel DOCK2-selective inhibitory peptide that suppresses B-cell line migration.
abstract: Dedicator of cytokinesis 2 (DOCK2) is a key molecule for lymphocyte activation and migration. DOCK2 interacts with Ras-related C3 botulinus toxin substrate 1 (Rac1, GTPase) and mediates the GDP-GTP exchange reaction, indicating that inhibitors against protein-protein interaction (PPI) between DOCK2 and Rac1 would be good drug candidates for treating immune-related disorders. Here, we report DOCK2-selective PPI inhibitory peptides discovered using random peptide T7 phage display technology. These peptides inhibited DOCK2 activity at nanomolar concentrations and were delivered to intracellular compartments by combination with cell-penetrating peptide (CPP). Consequently, one peptide, R4-DCpep-2(V2W/K4R/ox)-NH2(Ac-RRRRCWARYHGYPWCRRRR-NH2), inhibited migration in human B lymphocyte MINO cell line at IC50= 120 nM. To our knowledge, this is the first report of a DOCK2-selective peptide inhibitor; this study will contribute to the development of novel DOCK2-targeting immunosuppressive drugs.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: koutarou.sakamoto@takeda.com.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Komoike
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryokichi
authors.initials: R
authors.lastname: Koyama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Kadotani
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Asami
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Sakamoto
mesh_terms: D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002474:Cell-Free System; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D060066:Protein Interaction Maps; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D019151:Peptide Library; D010455:Peptides; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein
keywords: CPP; Cell migration; DOCK2; PPI; Peptide; Phage display