Drug Design and Synthesis for Orthopoxvirus Infections

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