The proposed research program aims to develop antiinfective agents that act on new or emerging targets, which recognize or process carbohydrate domains in their mechanism of action. The continuing emergence of drug-resistant strains of both bacteria and viruses warrants not only the development of new agents based on established molecular targets, but more importantly the investigation of new targets that have not yet been exploited for drug development. The proposal describes three main areas of research. The first is targeting the bacterial transglycosylase, one of the enzymatic functionalities involved in the assembly of the cell wall peptidoglycan. While the transpeptidase has long been established as the target of p-lactam antibiotics, the transglycosylase remains poorly understood, largely because of the difficulty of accessing its Lipid II substrate, and the lack of a high throughput assay. We will use our experience in expressing this enzyme, and our synthetic experience with Lipid II and related analogues, to develop a high-throughput assay and study in detail the structural determinants of the transglycosylation reaction. Results of this work will be used to design libraries of potential inhibitors, taking advantage of our recent developments in microtiter-based chemistry an in situ screening to rapidly access inhibitors. The second area is targeting the influenza virus neuraminidase and hemagglutinin. We will use our methodology for synthesis of fluoroglycosides to develop bifunctional inhibitors that target both viral proteins. With our collaborator, Ian Wilson, we will focus on the carbohydrate specificity of HA from virulent new avian flu strains. The third area will target CD1d for activation of NKT cells, which is a promising new approach to intervention in both bacterial and viral infections. With our collaborators Ian Wilson and Moriya Tsuji, we have begun to understand the structural basis for selective activation of adjuvant or immunosuppressive responses by glycosylceramide ligands. Using our synthetic methodology, we and our collaborators will continue to develop improved CD1d agonists and define the potential these compounds have in treating bacterial and viral infections. Antibiotic-resistant infections and emerging viruses such as the avian flu pose a significant worldwide threat.
Our research aims to discover new ways to combat these infections, and will result in effective new treatments to cure and prevent them in the future.
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