This is a proposal to identify and develop a new class of antiviral compounds, we call """"""""glucovirs"""""""", for the treatment of members of the flaviviridae family such as West Nile Encephalitis Virus, Yellow Fever (WNEV, YFV respectively) and Powassan viruses (PV) that have been identified as being of bioterror concern. The candidate compounds are imino sugar glucose mimetics (hence, """"""""glucovirs"""""""") that competitively inhibit the cellular endoplasmic reticular (EA) glycan-processing enzyme, glucosidase. We have shown that viruses that gain their envelopes from the ER, such as members of the flavi and hepadnavirus families, share a common vulnerable step in their life cycle: extreme dependency upon ER glucosidase function as compared with most cellular functions. Since the flaviviruses of bioterror potential are difficult or dangerous to grow in tissue culture, but the flavivirus family member bovine viral diarrhea virus (BVDV) is easily quantified in tissue culture, we have been using BVDV as a surrogate. We have already identified orally available glucovirs with in vitro selectivity indexes of 50, but flaws in these compounds make it desirable to identify compounds with better physical properties. Therefore, rationally designed glucosidase inhibitors will first be tested for the ability to inhibit BVDV, in a standard yield reduction assay. Compounds meeting a set criteria of selectivity will be tested for antiviral activity against YFV, WNEV and PV by our collaborator, in a tissue culture and, if appropriate, small rodent models. In future studies (beyond the discovery program), lead compounds, meeting synthesis and efficacy standards, will then be placed in a development pathway including animal PK/toxicity and ultimately, if appropriate, human trials.
| Chapman, Timothy M; Davies, Ieuan G; Gu, Baohua et al. (2005) Glyco- and peptidomimetics from three-component Joullie-Ugi coupling show selective antiviral activity. J Am Chem Soc 127:506-7 |
