Abstract for the RCE

Bacillus anthracis Host Interactions

Discovery of Subunit Vaccine Candidates                             against Glanders

Alphavirus Vaccines for Biodefense

Novel Genetic Tools for Viral Biodefense

Development and Evaluation of Human
                     Brucellosis Vaccines

Rapid Diagnostic Tools for Q Fever

New Diagnostic Methods for Accute Rickettsial
                      Infections

Risks and Interventions for Pandemic Influenza

Development of Novel Pseudoinfectious Flavivirus                             Vaccines

Development of Diagnostic Reagents for the detection
                            of Francisella and
                             Francisella Infection

Toward Control of Rift Valley Fever Virus
                             Replication

Novel Vaccine Technology for Biodefense

Nucleocapsid-specific Small Molecule Inhibitors
                             of the Bunyaviridae

New Technologies for Creating Affinity Reagents

New Opportunities Projects

Identification and Characterization of Novel
                             Flavivirus Antivirals

Biosafety Containment Training Program

Passive Immunotherapeutics for
                             Select Agents

Preclinical Testing of YF17D/LAS, a Bivalent
                              Vaccine for Lassa and
                             Yellow Fever

Identification and Characterization of Novel Flavivirus Antivirals

Collaborating Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX

Principal Investigator: Nigel Bourne, PhD

Co-Investigators:

a) Peter Mason, PhD – UTMB, Galveston, TX
b) Scott Gilbertson, PhD – UTMB, Galveston, TX

Expected Product: Safe and effective new antiviral agents for the treatment of flavivirus infections.

Description: Flaviviruses are the causative agents of a number of diseases of public health importance including West Nile encephalitis, yellow fever, dengue fever and Japanese encephalitis. However, current treatment options for these diseases are limited and there is a real need for new antiviral agents with specific activity against these viruses. The long-term objectives of this project are to meet this need by identifying and characterizing new small molecule compounds with broad spectrum activity against medically important flaviviruses. The project that we propose has three specific aims:

(1) High throughput screening identification of novel lead compounds. Using a West Nile virus (WNV) virus-like particle (VLP) assay that we have developed and which is suitable for use under low biocontainment conditions, we will conduct high-throughput screening of a large library of compounds at the National Screening Laboratory for the Regional Centers of Excellence. The data generated during screening will be analyzed and the most promising antiviral compounds identified. The activity of the selected compounds against WNV will be confirmed using live virus assays and their broad spectrum anti-flavivirus activity determined in live virus assays with dengue virus and yellow fever virus.

(2) Medicinal chemistry modification and iterative in vitro antiviral testing. Based on their activity against all three flaviviruses, toxicity profiles and potential for chemical modification, three compounds will be identified as leads and will undergo a series of medicinal chemical modifications in the Parallel Synthesis and Medicinal Chemistry facility at UTMB. Each round of chemical modifications will involve the synthesis of a small number of compounds which will then undergo rapid in vitro toxicity and antiviral activity testing in live virus assays. This process will result in several rounds of controlled iterative synthesis and evaluation that we expect will lead to the identification of more potent antiviral compounds.

(3) In vivo evaluation of activity in a small animal model of WNV encephalitis. In this aim the two most promising compounds identified during the chemical modification studies will be evaluated for activity in vivo using a mouse model of WNV encephalitis.

Thus by the end of the project period we expect to have identified a number of new compounds with broad spectrum activity against medically important flaviviruses and to have undertaken preliminary studies to evaluate their potential therapeutic utility in a well defined animal model with virologic and pathologic endpoints that are relevant to those seen in the clinical situation.