The ability of HIV to enter a latent state creates a fundamental obstacle to the eradication of HIV-1 infection by anti-retroviral therapy and has prompted continued interest in developing inhibitors that block the re-emergence of latent proviruses. The goal of this research project is to continue the development of new antiviral leads that target the HIV TAR RNA, and inhibit at the same time reverse transcription and transcriptional elongation from the HIV-1 promoter. Such an inhibitor would be able to block viral replication in both acutely and chronically infected cells and target the reservoir of slowly replicating viruses that persists in the presence of Highly Active Anti Retroviral Therapy (HAART). In the previous funding period, we have identified a new cyclic peptide lead that binds to the HIV TAR RNA with unprecedented activity by expanding peptide chemistry to include un-natural peptidic side chains. The lead peptidomimetic compounds penetrate cellular membranes and inhibit viral replication in primary lymphocytes with activity comparable to nevirapine. We have demonstrated that the antiviral activity coincides with inhibition of both reverse transcription and transcriptional elongation. We now propose to: 1. Optimize the antiviral activity of the cyclic peptide mimetics of the Tat protein to inhibit the function of TARby exploiting additional un-natural peptide side chains and modifications of the peptide backbone 2. Establish the molecular mechanism of action of the peptide leads 3. Generate resistance mutants to fully validate the molecular targets of these anti-viral leads

Public Health Relevance

The discovery of new inhibitors of HIV viral replication that function by novel mechanisms would provide alternative to existing treatment that escape the emergence of resistance, and would interfere with the emergence of the virus from the latent phase.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sakalian, Michael
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University of Washington
Schools of Arts and Sciences
United States
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Abulwerdi, Fardokht A; Shortridge, Matthew D; Sztuba-Solinska, Joanna et al. (2016) Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA. J Med Chem 59:11148-11160
Bottini, Angel; De, Surya K; Wu, Bainan et al. (2015) Targeting Influenza A Virus RNA Promoter. Chem Biol Drug Des 86:663-73
Shortridge, Matthew D; Varani, Gabriele (2015) Structure based approaches for targeting non-coding RNAs with small molecules. Curr Opin Struct Biol 30:79-88
Hopping, Gene; Kellock, Jackson; Barnwal, Ravi Pratap et al. (2014) Designed ?-sheet peptides inhibit amyloid formation by targeting toxic oligomers. Elife 3:e01681
Lee, Mi-Kyung; Bottini, Angel; Kim, Meehyein et al. (2014) A novel small-molecule binds to the influenza A virus RNA promoter and inhibits viral replication. Chem Commun (Camb) 50:368-70
Musiani, Francesco; Rossetti, Giulia; Capece, Luciana et al. (2014) Molecular dynamics simulations identify time scale of conformational changes responsible for conformational selection in molecular recognition of HIV-1 transactivation responsive RNA. J Am Chem Soc 136:15631-7
Bardaro Jr, Michael F; Shajani, Zahra; Patora-Komisarska, Krystyna et al. (2009) How binding of small molecule and peptide ligands to HIV-1 TAR alters the RNA motional landscape. Nucleic Acids Res 37:1529-40
Davidson, Amy; Leeper, Thomas C; Athanassiou, Zafiria et al. (2009) Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. Proc Natl Acad Sci U S A 106:11931-6