New drug targets are important to study to find new and more effective therapies to alleviate human disease. Currently, RNA and associated RNA-binding proteins are significantly underutilized as a potential target for drug development: most likely because there exists a lack of basic knowledge about how one should design a molecule to target these structures. In our research, the RNA-binding properties of sidechain-functionalized polyamines are being examined with two important RNA targets: TAR RNA and RRE RNA of HIV. Molecules that bind to these RNAs can potentially shut down replication of the virus. The basic knowledge developed from this work will ultimately be applicable to other RNA targets, and will provide a general set of guidelines for designing molecules that selectively bind a folded RNA structure. We identified a new version of our molecules that binds extremely well to TAR RNA and blocks association of the tat protein. In the past year, we have pursued the development of a small molecule to interfere with nucleocapid protein 7, NCp7, and its association in packaging viral HIV RNA. Interfering with this process is another strategy to interfere with HIV's progression and our publication the past year in Nature Chemical Biology shows the mechanism of the small molecule in preventing HIV replication involves a unique reacylation pathway.

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Ugaonkar, Shweta R; Clark, Justin T; English, Lexie B et al. (2015) An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission. J Pharm Sci 104:3426-39
Pokorski, Jonathan K; Appella, Daniel H (2012) Combinatorial Synthesis, Screening, and Binding Studies of Highly Functionalized Polyamino-amido Oligomers for Binding to Folded RNA. J Nucleic Acids 2012:971581
Kumar, Sunil; Kellish, Patrick; Robinson Jr, W Edward et al. (2012) Click dimers to target HIV TAR RNA conformation. Biochemistry 51:2331-47
Miller Jenkins, Lisa M; Ott, David E; Hayashi, Ryo et al. (2010) Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer. Nat Chem Biol 6:887-9
Wang, Deyun; Iera, Jaclyn; Baker, Heather et al. (2009) Multivalent binding oligomers inhibit HIV Tat-TAR interaction critical for viral replication. Bioorg Med Chem Lett 19:6893-7
Waters, Marcey L; Appella, Daniel H (2009) Mimicking nature: from fundamentals to applications. Curr Opin Chem Biol 13:641-2