Inhibition of the RNA-dependent transactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37.
Human immunodeficiency virus type 1 (HIV-1) is unique in that it encodes its own transcriptional activator Tat, which specifically binds to the viral mRNA sequence TAR (transactivation response) element and activates viral transcription at the step of elongation as well as initiation. We recently reported that fluoroquinoline derivatives inhibited HIV-1 replication most likely by blocking viral transcription. In this report, we investigated the mechanism of action of one such compound 7-(3, 4-dehydro-4-phenyl-1-piperidinyl)-1, 4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carbox ylic acid (K-37). We demonstrated that K-37 inhibited not only Tat but also other RNA-dependent transactivators. No effect was observed with DNA-dependent transactivators such as p65 (NF-kappaB) and Gal4VP16. Moreover, K-37 did not inhibit carboxyl-terminal domain (CTD)-kinase activities of CDK-activating kinase (CAK) and positive transcription elongation factor b (P-TEFb), which are known to be involved in Tat-mediated transactivation at the step of transcriptional elongation. It is suggested that RNA-mediated transactivation may involve a common unknown factor to which K-37 directly interacts. Since K-37 did not appear to block DNA-mediated transactivation and thus did not show strong nonspecific cytotoxicity as reported previously, K-37 and its derivative compounds are considered to be feasible candidates for a novel AIDS therapy.
Okamoto
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Department of Molecular Genetics, Nagoya City University Medical School, Nagoya, 467-8601, Japan.
Cujec
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Okamoto
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Peterlin
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Baba
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Okamoto
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D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002460:Cell Line; D004279:DNA, Viral / Q000502:physiology; D024841:Fluoroquinolones; D015696:Gene Products, tat / Q000037:antagonists & inhibitors; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D012367:RNA, Viral / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D004279:DNA, Viral; D024841:Fluoroquinolones; D015696:Gene Products, tat; D047428:Protein Kinase Inhibitors; D012367:RNA, Viral; C411922:fluoroquinoline K-37; D054322:tat Gene Products, Human Immunodeficiency Virus; D011494:Protein Kinases; C060137:carboxy-terminal domain kinase