Targeting RNA With Small Molecules: SL3 of HIV -1 Psi-Rna

153 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.SL3 RNA of HIV-1 is the principal packaging determinant through its interaction with viral nucleocapsid protein, NCp7. Since SL3 is not a target of current anti-HIV therapeutics, the discovery of small molecules that target SL3 would not only expand the understanding of RNA recognition by small molecules, but could also lead to discovery of novel anti-viral drugs. This dissertation describes the identification and evaluation of small molecule ligands of SL3. Chapter one introduces RNA as a therapeutic target, detailing the basis, challenges and strategies for targeting RNA with small molecules. Chapter two describes how molecules that bind to SL3 RNA were identified using sequentially the docking programs DOCK and AutoDock, followed by MD simulations. These studies revealed nine RNA ligands, four of which are selective for SL3 RNA. Chapter three describes how a combination of virtual screening and high-throughput screening strategies was used to identify SL3 binders. These studies revealed sixteen compounds with micromolar affinities for RNA, two of which are selective for binding SL3, and another four disrupted NCp7-SL3 interactions. The last chapter describes how a combination of rational structure-based design, molecular modeling, and docking studies was used to create a 24-membered compound library. A subset of the library was then synthesized and evaluated. All eleven compounds evaluated showed low micromolar affinities for SL3 RNA including two peptide-nucleic acid conjugates that disrupted NCp7-SL3 complex with sub-micromolar inhibition constants.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD