title: Oxadiazols: a new class of rationally designed anti-human immunodeficiency virus compounds targeting the nuclear localization signal of the viral matrix protein.
abstract: Despite recent progress in anti-human immunodeficiency virus (HIV) therapy, drug toxicity and emergence of drug-resistant isolates during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the process of nuclear translocation of the HIV preintegration complex. Previously we described a class of arylene bis(methylketone) compounds that inhibit HIV-1 nuclear import by targeting the nuclear localization signal (NLS) in the matrix protein (MA). Here we report a different class of MA NLS-targeting compounds that was selected using computer-assisted drug design. The leading compound from this group, ITI-367, showed potent anti-HIV activity in cultures of T lymphocytes and macrophages and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue. The virus carrying inactivating mutations in MA NLS was resistant to ITI-367. Analysis by real-time PCR demonstrated that the compound specifically inhibited nuclear import of viral DNA, measured by two-long terminal repeat circle formation. Evidence of the existence of this mechanism was provided by immunofluorescent microscopy, using fluorescently labeled HIV-1, which demonstrated retention of the viral DNA in the cytoplasm of drug-treated macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for further development.
authors.affiliation: International Therapeutics Inc., Seattle, Washington, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Haffar
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubrovsky
authors.forename: Richard
authors.initials: R
authors.lastname: Lowe
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Godden
authors.forename: Christophe
authors.initials: C
authors.lastname: Vanpouille
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015683:Gene Products, gag / Q000737:chemistry; D015488:HIV Antigens / Q000737:chemistry; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009000:Monocytes; D019913:Nuclear Localization Signals / Q000187:drug effects; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014764:Viral Proteins / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D015683:Gene Products, gag; D015488:HIV Antigens; D019913:Nuclear Localization Signals; D010069:Oxadiazoles; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1