NMR AND DESIGN OF ANTISENSE AND RIBOZYME AGENTS TO HIV

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Multi-dimensional 1H homonuclear and heteronuclear NMR, molecular modeling, molecular dynamics and perturbational free energy calculations will be used to define the three-dimensional structure of antisense and ribozyme oligonucleotide analogues, metal (including cis-platinum) dithiophosphate oligonucleotide agents and nucleic acid-agent complexes targeted towards the human immunodeficiency (AIDS) virus. Diasteromerically pure methylphosphonate and phosphorothioates and novel phosphorodithioates oligonucleotide analogues will be synthesized and the three-dimensional structure of their complexes with complementary single- and double-stranded oligonucleotides will be determined to understand the in vitro and in vivo biological activities that will also be obtained. Various RNA and DNA binding and gene regulatory agents will be synthesized using established synthetic organic methods. We will take an integrated approach towards the rational design of agents targeted towards the human immunodeficiency virus (HIV) utilizing high resolution nuclear magnetic resonance (NMR) spectroscopy, computational biochemistry, and molecular modeling of biomolecules. This support will provide funding of the research base for an NSF Biological Facilities Center in Bimolecular NMR, Structure and Design and the NMR Structural Biology Core of an NIH designated AIDS Research Center already established at Purdue. NMR spectroscopy will provide an important probe of the molecular structure and dynamics of biological macromolecules. Ultimately we hope to rationally design and construct agents that will provide potential irreversible inhibition of HIV gene transcription.