title: The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
abstract: The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Murakami
authors.forename: Sei
authors.initials: S
authors.lastname: Kumakura
authors.forename: Toru
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Makiko
authors.initials: M
authors.lastname: Hamatake
authors.forename: Kazu
authors.initials: K
authors.lastname: Okuma
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Toma
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
authors.forename: Mikiro
authors.initials: M
authors.lastname: Yanaka
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4