Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra- and pentapeptide-scaffolds towards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis.
The chemokine receptor, CXCR4, is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 system plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, etc. This system has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA) and pulmonary fibrosis. Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were characterized as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. Based on our knowledge of pharmacophores of T140, CXCR4 antagonists, such as FC131, were previously found by the efficient utilization of cyclic pentapeptide libraries. This review article focuses on our recent research on the development of low molecular weight CXCR4 antagonists including FC131 analogs, in which structural tuning of the cyclic peptide ring and chemical modifications were performed for an increase in potency and a reduction of the peptide character.
Tamamura
Hirokazu
H
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan. tamamura.mr@tmd.ac.jp
Tsutsumi
Hiroshi
H
Masuno
Hiroyuki
H
Fujii
Nobutaka
N
D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009369:Neoplasms / Q000473:pathology*; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4