title: A novel small molecular weight compound with a carbazole structure that demonstrates potent human immunodeficiency virus type-1 integrase inhibitory activity.
abstract: The integration of reverse transcribed proviral DNA into a host genome is an essential event in the human immunodeficiency virus type 1 (HIV-1) replication life cycle. Therefore, the viral enzyme integrase (IN), which plays a crucial role in the integration event, has been an attractive target of anti-retroviral drugs. Several IN inhibitory compounds have been reported previously, yet none has been successful in clinical use. To find a new, more successful IN inhibitor, we screened a diverse library of 12 000 small molecular weight compounds randomly by in vitro strand-transfer assay. We identified a series of substituted carbazoles that exhibit strand-transfer inhibitory activity at low micromolar concentrations. Of these, the most potent compound exhibited an IC50 of 5.00+/-3.31 microM (CA-0). To analyse the structural determinants of strand-transfer inhibitory activity of the carbazole derivatives, we selected 23 such derivatives from our compound library and performed further analyses. Of these 23 compounds, six showed strong strand-transfer inhibition. The inhibition kinetics analyses and ethidium bromide displacement assays indicated that the carbazole derivatives are competitive inhibitors and not intercalators. An HeLa4.5/LTR-nEGFP cell line was employed to evaluate in vitro virus replication inhibition of the carbazole derivatives, and IC50 levels ranged from 0.48-1.52 microM. Thus, it is possible that carbazole derivatives, which possess structures different from previously-reported IN inhibitors, may become novel lead compounds in the development of IN inhibitors.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Hua
authors.initials: H
authors.lastname: Yan
authors.forename: Tomoko Chiba
authors.initials: TC
authors.lastname: Mizutani
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nomura
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Takakura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Hideka
authors.initials: H
authors.lastname: Miura
authors.forename: Masako
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Tatsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugiura
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009838:Oligodeoxyribonucleotides; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D019427:HIV Integrase