Presents the Friday Keck Center Teleconference*
Thioaptamers
for Diagnostics and Therapeutics in Biodefense and Emerging Infectious Diseases
David Gorenstein, Ph.D.,
Charles Marc Pomerat Professor of Biological Sciences, Associate Dean of Research
University of Texas Medical Branch at Galveston
4:00 pm Friday
Nov. 30th , 2007
(Refreshments at 3:45)
5.521 Levin Hall
Abstract: RNA and DNA oligonucleotides can act as "aptamers," (i.e., as direct in vivo binders selected from large combinatorial libraries) for a number of proteins and other targets. We have developed both in vitro enzymatic combinatorial selection and split-synthesis chemical combinatorial methods to identify phosphorothioate-modified oligonucleotide "thioaptamers" to a number of different infectious disease targets for both diagnostics and therapeutics. Importantly, it has been noted that sulfurization of the phosphoryl oxygens of oligonucleotides often leads to their enhanced binding to numerous proteins. We have developed monothiophosphate and dithiophosphate backbone-modified thioaptamers that bind to proteins involved in the immune response, as well as to other proteins of the proteome. We are currently utilizing bead-based high-throughput screening of thioaptamer bead libraries to select thioaptamers for the development of thioaptamer-based proteomics arrays and microfluidics chips to identify and quantify proteins and protein complexes associated with critical signaling and immune response pathways relating to viral infection and shock. We believe that these methods will provide an important diagnostic tool to identify and quantify the differential expression of key proteins in response to pathogens of concern for bioterrorism and emerging infectious diseases. In particular we describe the development of thioaptamers targeting key transcription factors (e.g., NF-kB and AP-1) involved in the inflammatory response. Using NMR spectroscopic methods, we have solved the solution structure of domain III, the receptor-binding domain, of the envelope protein of several flaviviruses, including West Nile, Omsk Hemorrhagic Fever, and Dengue. We demonstrate that selected thioaptamers show promise as therapeutic agents targeting these flaviviruses and hemorrhagic fever arenaviruses. (http://www.hbcg.utmb.edu/faculty/gorenstein/)
