title: Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides.
abstract: Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC(90) concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.
authors.affiliation: Wohl Virion Centre, MRC Centre for Medical Molecular Virology, UCL, London, UK.
authors.forename: Belinda
authors.initials: B
authors.lastname: Loh
authors.forename: Luciano
authors.initials: L
authors.lastname: Vozzolo
authors.forename: B James
authors.initials: BJ
authors.lastname: Mok
authors.forename: Chien Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fitzmaurice
authors.forename: Stephen
authors.initials: S
authors.lastname: Caddick
authors.forename: Ariberto
authors.initials: A
authors.lastname: Fassati
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D007555:Isoxazoles; D013449:Sulfonamides