The project involves the synthesis and testing of a variety of antiviral compounds that are directed against NIAID Category A, B &C Priority Pathogens. The parent compounds have been shown to have antiviral properties and we propose to synthesize a variety of analogs of the parent compounds in order to optimize their antiviral activities and pharmaceutical properties. To determine the suitability of these compounds for oral delivery, compounds will be tested for the biopharmaceutical properties of 1) solubility and stability in gastric and intestinal buffers and 2) intestinal permeability. Further, transport studies will be performed to determine the mechanism of intestinal uptake. To determine the metabolism of compounds (or """"""""activation"""""""" in the case of prodrugs) in the target tissue, compounds will be screened for stability in a variety of tissue homogenates including intestinal and liver homogenates, virally-infected cell homogenates, and purified activation enzymes (e.g., BPHL). To determine the activity of the compounds, they will be screened for anti-viral activity against a variety of viral targets in tissue culture models. Using gene chip analysis and proteomic methodologies, the effect of the prodrug compounds will be evaluated in virally-infected cell based systems and correlated with the observed activities and expression levels of relevant transporters and potential activation enzymes. Finally, lead candidates that arise from this screening process will be tested for bioavailability in rats. Initial toxicology testing (14 day) will be performed on leads showing good bioavailability.
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