A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity.
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.
Ichiyama
Kozi
K
Department of Molecular Virology, Bio-Response, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Yokoyama-Kumakura
Sei
S
Tanaka
Yuetsu
Y
Tanaka
Reiko
R
Hirose
Kunitaka
K
Bannai
Kenji
K
Edamatsu
Takeo
T
Yanaka
Mikiro
M
Niitani
Yoshiaki
Y
Miyano-Kurosaki
Naoko
N
Takaku
Hiroshi
H
Koyanagi
Yoshio
Y
Yamamoto
Naoki
N
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
D019380:Anti-HIV Agents; C473941:KRH 1636; D011725:Pyridines; D019718:Receptors, CXCR4; D001120:Arginine