The long-term goal of this research is to design new compounds to inhibit UDP-galactopyranose mutase (UGM), a key enzyme in the biosynthesis of galactofuranose (Galf). Galf is an important component of the cell wall and glycan complexes found on the cell surface of many eukaryotic pathogens. It has been shown that UGM is essential for growth in helminths and is an important virulence factor in Aspergillus fumigatus and Leishmania major. Because of its importance in pathogenesis and its absence in humans, UGM is a target for the development of novel therapeutics against multiple eukaryotic pathogens. Previous studies by the PIs have determined that eukaryotic UGMs contain a unique ADP binding site and novel mechanistic role for the flavin cofactor. The goals of this project are to identify inhibitors of eukaryotic UGMs, characterize the molecular mechanisms of inhibition using biochemical and structural methods, and test the effects of these compounds on microbial and human cells. A subset of compounds having the highest potency and best safety profiles will be used as the starting structures for iterative optimization using structure-guided medicinal chemistry approaches to increase binding affinity, specificity, and drug-likeness. The team of investigators has expertise in UGM biochemistry and high-throughput screening (Sobrado), X-ray crystallography of UGM (Tanner), medicinal/synthetic organic chemistry (Gates), and toxicology/pharmacology (Ehrich). A major innovation of this project is that we direct high-throughput screening to the heretofore unexplored ADP pocket of eukaryotic UGMs. The molecular environment within this site is unique to and conserved by eukaryotic UGMs and, thus, the discovered compounds have the potential to inhibit multiple eukaryotic UGMs.
Infections by eukaryotic pathogens, such as fungi, parasites, and nematodes cause a multitude of diseases, including aspergillosis, Chagas? disease, leishmaniasis, elephantiasis, and river blindness. Despite the significant worldwide mortality and human suffering caused by these (mostly neglected) diseases, there are no efficacious drug treatments or vaccinations available to treat them. This project will discover inhibitors of UDP- galactopyranose mutase, the central enzyme in the biosynthesis of galactofuranose, as a first step toward the development of novel therapeutics for eukaryotic pathogens.
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