title: A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity.
abstract: A low molecular weight nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic (X4) HIV type 1 (HIV-1) in MT-4 cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXC chemokine receptor (CXCR)4 coreceptor but not via CC chemokine receptor 5. It also inhibited binding of the CXC chemokine, stromal cell-derived factor 1alpha, to CXCR4 specifically and subsequent signal transduction. KRH-1636 prevented monoclonal antibodies from binding to CXCR4 without down-modulation of the coreceptor. The inhibitory effect against X4 viral replication by KRH-1636 was clearly reproduced in the human peripheral blood lymphocytesevere combined immunodeficiency mouse system. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography MS in the plasma. Thus, KRH-1636 seems to be a promising agent for the treatment of HIV-1 infection.
authors.affiliation: Department of Molecular Virology, Bio-Response, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Kozi
authors.initials: K
authors.lastname: Ichiyama
authors.forename: Sei
authors.initials: S
authors.lastname: Yokoyama-Kumakura
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Kunitaka
authors.initials: K
authors.lastname: Hirose
authors.forename: Kenji
authors.initials: K
authors.lastname: Bannai
authors.forename: Takeo
authors.initials: T
authors.lastname: Edamatsu
authors.forename: Mikiro
authors.initials: M
authors.lastname: Yanaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Niitani
authors.forename: Naoko
authors.initials: N
authors.lastname: Miyano-Kurosaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaku
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007408:Intestinal Absorption; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; C473941:KRH 1636; D011725:Pyridines; D019718:Receptors, CXCR4; D001120:Arginine