Oxadiazols: a New Class of Rationally Designed Anti-Human Immunodeficiency Virus Compounds Targeting the Nuclear Localization Signal of the Viral Matrix Protein

Oxadiazols: a New Class of Rationally Designed Anti-Human Immunodeficiency Virus Compounds Targeting the Nuclear Localization Signal of the Viral Matrix Protein Omar Haffar 1 , Larisa Dubrovsky 2 , Richard Lowe 1 , Reem Berro 3 , Fatah Kashanchi 3 , Jeffrey Godden 4 , Christophe Vanpouille 2 , Jürgen Bajorath 4 , 5 , and Michael Bukrinsky 2 , * 1 International Therapeutics Inc., Seattle, Washington 4 Albany Molecular Research-Bothell Research Center (AMRI-BRC), Bothell, Washington 5 Department of Biological Structure, University of Washington, Seattle, Washington 2 Department of Microbiology and Tropical Medicine, The George Washington University, Washington, D.C. 3 Department of Biochemistry and Molecular Biology, The George Washington University, Washington, D.C. 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.