Inhibition of human immunodeficiency virus replication by RD6-Y664, a novel benzylhydroxylamine derivative.
We have examined novel benzylhydroxylamine derivatives for their inhibitory effects on the replication of human immunodeficiency virus (HIV) in cell cultures. Among the series, O-(2-chloro-6-fluorobenzyl)hydroxylamine (RD6-Y664) was found to be the most potent inhibitor of HIV-1. The EC50 for HIV-1 strain IIIB was 1.6 micrograms/ml with a selectivity index greater than 38 in MT-4 cells. It also inhibited the replication of other HIV strains including a non-nucleoside reverse transcriptase (RT) inhibitor-resistant mutant, a nucleoside RT inhibitor-resistant mutant and HIV-2, in acutely infected cells. However, the compound did not affect HIV-1 production in chronically infected cells. A time-of-addition experiment and detection of proviral DNA synthesis suggested that RD6-Y664 targeted an early step of the viral replication cycle, presumably a process prior to reverse transcription. In fact, an assay for HIV-1 RT revealed that the compound did not suppress enzyme activity. Furthermore, RD6-Y664 did not show any inhibition of gp120-CD4 interaction, or binding of anti-CXCR4 antibody to CXCR4.
Okamoto
M
M
Rational Drug Design Laboratories, Fukushima, Japan. ma-okamoto@mb.6.skk-net.com
Fujiwara
M
M
Kodama
E
E
Yamamoto
O
O
Shigeta
S
S
Mitsuya
H
H
Konno
K
K
Yokota
T
T
Baba
M
M
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D006898:Hydroxylamines; C120098:O-(2-chloro-6-fluorobenzyl)hydroxylamine; D015215:Zidovudine