Todd L. Lowary
Our research program is focused in the areas of synthetic chemistry (with a particular emphasis in carbohydrate chemistry), the conformational analysis of oligosaccharides and the design of novel therapeutic agents that act by inhibiting carbohydrate-processing enzymes. Students and postdoctoral fellows in the group use synthetic chemistry to prepare compounds with interesting biological activities and then have the opportunity to use them in either biochemical or conformational studies.
The primary research focus is directed ultimately towards the identification of new drugs for the treatment of tuberculosis. Our approach is to develop inhibitors of the enzymes that assemble the polysaccharide portions of the protective cell wall of the organism responsible for this disease, Mycobacterium tuberculosis. These polysaccharides are unique in that they are comprised largely of monosaccharides in the furanose ring form. The synthesis of these compounds has been largely neglected by synthetic chemists and our efforts involve both total synthesis and the development of new synthetic methods.
We have completed the total synthesis of a 22-residue oligosaccharide that is an important motif (below) found in the mycobacterial cell wall and fragments of this oligosaccharide, and related analogues, are currently being synthesized and explored in the development of novel vaccines for the prevention of tuberculosis. As part of our involvement in the Alberta Ingenuity Centre for Carbohydrate Science we are also working towards the characterization of glycosyltransferases involved in mycobacterial cell wall biosynthesis.
A second focus of the lab is the synthesis and biochemical evaluation of novel inhibitors of topoisomerases. These enzymes that play important roles in DNA transcription and RNA translation, and are the targets of the anti-cancer drugs campothecin and doxorubicin.
A third area involves the synthesis of novel analogs of rhamnolipids and their evaluation and anti-bacterial agents and biosurfactants.
In addition to these synthetic and biochemical efforts, we are also actively working towards understanding the solution conformation of these molecules. Our investigations in this area are multifaceted and involve the use of chemical synthesis of 13C-labeled carbohydrates, as well as NMR and computational studies. More information about these projects can be found our the group webpage.
Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. "Synthesis of the Docosanasaccharide Arabinan Domain of Mycobacterial Arabinogalactan and a Proposed Octadecasaccharide Biosynthetic Precursor" J. Am. Chem. Soc. 2007, 129, 9885-9901.
Completo, G. C.; Lowary, T. L. "Synthesis of galactofuranose-containing acceptor substrates for mycobacterial galactofuranosyltransferases" J. Org. Chem. 2008, 73, 4513-4525.
Szczepina, M. G.; Zheng, R. B.; Completo, G. C.; Lowary, T L.; Pinto, B. M. "STD-NMR Studies Suggest that Two Acceptor Substrates for GlfT2, a Bifunctional Galactofuranosyltransferase Required for the Biosynthesis of Mycobacterium tuberculosis Arabinogalactan, Compete for the Same Binding Site" ChemBioChem 2009, 10, 2052-2059.
Murase, T.; Zheng, R. B.; Joe, M.; Bai, Y.; Marcus, S. L.; Lowary, T. L.; Ng*, K. K. S. "Structural insights into host recognition of mycobacterial polysaccharides" J. Mol. Biol. 2009, 392, 381-392.
Hou, D.; Taha, H. A.; Lowary, T. L. "2,3-Anhydrosugars in Glycoside Bond Synthesis. Mechanism of 2-Deoxy-2-Thioaryl Glycoside Formation" J. Am. Chem. Soc. 2009, 131, 12937-12948.