Searching for inhibitors of UDP-sugar utilizing enzymes from an aminothiazole library

MEDI 280

Emily Dykhuizen, edykhuiz@chem.wisc.edu, Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave, Madison, WI 53706, John H. Phillips, jphillip@chem.wisc.edu, Department of Chemisty, University of Wisconsin - Madison, 1101 University Ave, Madison, WI 53706, and Laura L. Kiessling, Departments of Chemistry and Biochemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706.
Uridine 5'-diphospho (UDP)-sugars are substrates for many enzymes. Selective inhibitors of UDP-sugar utilizing enzymes would be invaluable tools in dissecting the regulation and function of the numerous and diverse glycoconjugates found in living systems. To design selective inhibitors, we have used computer modeling; our studies suggest that the 2-aminothiazole scaffold will occupy the UDP-Gal binding region in the active site of an α1,3-galactosyltransferase. To test this hypothesis, we synthesized a 2000--member library of neutral, drug-like compounds using a one-bead one-compound approach. To identify selective inhibitors, we developed a general high-throughput screen based on fluorescence anisotropy. Using this assay, we screened our library against UDP-galactopyranose mutase (UGM), the enzyme responsible for the isomerization of UDP-galactopyranose to UDP-galactofuranose; the latter is a key building block for the cell wall of Mycobacterium tuberculosis. We have identified hits and are synthesizing directed libraries with key binding elements. Additionally, screens against α1,3-galactosyltransferase are underway.
 

Medicinal Chemistry Award Symposium
9:00 AM-12:10 PM, Tuesday, 12 September 2006 Moscone Center -- Room 102, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006