Developmental of antiviral agents has proved to be difficult due to the close interactions of viruses with host macromolecular machinery and intracellular replication of viruses. As such, few antiviral agents have made it to the commercial marketplace. In particular, antiviral agents have met with very limited success against viruses that are emerging diseases and/or potential biological weapons. We have taken a rational approach to the design of antiviral agents, and designed thioaptamers for use of antiviral agents. Aptamers are nucleic acid molecules that have been selected from random or high-sequence diversity libraries on their ability to tightly bind to the target (such as a protein) of interest. An iterative process known as in vitro selection is then used to enrich the library for species with high affinity to the target. Using combinatorial selection of phosphorothioate oligonucleotide aptamers, we have selected a dithioated aptamer (XBY-6) that selectively binds transcription factor NF-kB with the aim of using this thioaptamer to modulate the host immune response to infection. In addition, we have found that a second dithioated aptamer XBY-S2, that selectively binds to another transcription factor, Activator Protein 1. Using the NIAID Category B pathogen West Nile virus as a model system for flaviviruses we have found that XBY-6 and XBY-S2 will modulate an otherwise lethal challenge of West Nile virus in the mouse model and protect 50-80% of mice from death. The objective of this cooperative grant application is to elucidate the mechanism(s) of action of XBY-6 and XBY-S2, optimize the antiviral activity of XBY-6 and XBY-S2 in mice, and undertake preclinical testing for safety and efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI060616-02
Application #
6806481
Study Section
Special Emphasis Panel (ZAI1-ALR-M (M3))
Program Officer
Greenfield, Teri L
Project Start
2003-09-30
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$477,788
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Yang, Xianbin; Wang, He; Beasley, David W C et al. (2006) Selection of thioaptamers for diagnostics and therapeutics. Ann N Y Acad Sci 1082:116-9