title: Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents.
abstract: The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathologic physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). The interaction between CXCL12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutic target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsutsumi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Takanobu
authors.initials: T
authors.lastname: Araki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D009842:Oligopeptides; D010455:Peptides; D019718:Receptors, CXCR4; C116977:T140 peptide