Among all the possible biologic threats to humans, smallpox represents one of the greatestpotential hazards. While vaccination is the ideal modality for disease prevention, adverse eventsare high and mortality can be anticipated. As a consequence, the development of antiviral drugs forthe treatment of smallpox as well as other members of the orthopoxvirus family (i.e. monkey poxand variola) are essential. This effort requires evaluation of new potential drug targets, highthroughput screening of potential antiviral compounds and design of new antiviral compoundsbased on the structure of sensitive target proteins. Program 2 of the SERCEB is directed toward therapid development of antiviral therapies to treat orthopoxvirus diseases and consists of threeprojects. In Project 1, vaccinia virus enzymes will be expressed in the laboratories of Drs. R. Moyerand M. Luo and submitted to Core F (structural biology) for three-dimensional structuredetermination. Project 2 under the leadership of Dr. E. Kern will utilize purified vaccinia virusenzymes from Project 1 for the development of high throughput antiviral screening assays tocomplement already existent cell-based screening assays. Other potential therapeutics will bedeveloped by screening large collections of existing compounds which have been secured throughletters of collaboration with Gilead and Chimerix. Potentially active compounds will be furtherevaluated in animal models. Project 3, led by Drs. Secrist and Toone, three dimensional structuredata to develop novel therapeutics through synthetic chemistry. Deliverables from this program areanticipated within the first year. Specifically, antiviral activity has been demonstrated for twoclasses of compounds, activity established in animal models and a synthetic chemistry program toimprove activity initiated. Candidate drugs that meet preclinical toxicology specifications will beevaluated through Dr. Whitley's NIAID Collaborative Antiviral Study Group.
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