Skip to main content
Article thumbnail
Location of Repository

A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity

By Masanori Baba, Osamu Nishimura, Naoyuki Kanzaki, Mika Okamoto, Hidekazu Sawada, Yuji Iizawa, Mitsuru Shiraishi, Yoshio Aramaki, Kenji Okonogi, Yasuaki Ogawa, Kanji Meguro and Masahiko Fujino

Abstract

The β-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of β-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6–3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 1999
OAI identifier: oai:pubmedcentral.nih.gov:21923
Provided by: PubMed Central
Sorry, our data provider has not provided any external links therefore we are unable to provide a link to the full text.

Suggested articles


To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.