Novel HIV-1 integrase inhibitors derived from quinolone antibiotics.
The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.
Sato
Motohide
M
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Motomura
Takahisa
T
Aramaki
Hisateru
H
Matsuda
Takashi
T
Yamashita
Masaki
M
Ito
Yoshiharu
Y
Kawakami
Hiroshi
H
Matsuzaki
Yuji
Y
Watanabe
Wataru
W
Yamataka
Kazunobu
K
Ikeda
Satoru
S
Kodama
Eiichi
E
Matsuoka
Masao
M
Shinkai
Hisashi
H
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004279:DNA, Viral / Q000737:chemistry; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase