Mycobacterium tuberculosis (Mtb) is the etiological agent of Tuberculosis (TB). TB has become the leading cause of death worldwide due to an infectious agent. Increasingly, Mtb is becoming resistant to existing chemotherapy. One potential target for treating Mtb is the glycoside hydrolase-like phosphorylase Mtb GlgE which plays a role in α-glucan biosynthesis. The enzyme uses maltose-1-phosphate (M1P) and the growing α-glucan chain as substrates to catalyze α-glucan chain extension. We have utilized the closely related enzyme Streptomyces coelicolor (Sco) GlgEI-V279S as a model enzyme for inhibitor development. Sco GlgEI-V279S has nearly identical active site topology in comparison to Mtb GlgE; however, Sco GlgEI-V279S has an advantage over Mtb GlgE in that it crystallizes readily as a complex with small molecule inhibitors to yield high resolution X-ray structures. We have designed a number of glycomimetics based on M1P and have solved their structures in complex with Sco GlgEI-V279S using X-ray crystallography. The resulting data has been used in combination with in silico docking to identify new inhibitors of Sco GlgEI-V279S. Thus, far we have identified several glycosides related to M1P that inhibit the enzyme and successfully co-crystallized with Sco GlgEI-V279S. The synthesis of these targets and the structural studies will be discussed as well as ongoing efforts to identify more drug-like glycomimetics of M1P with improved potency.

Glycomimetics of maltose-1-phosphate as inhibitors of the glycoside hydrolase-like enzyme Streptomyces coelicolor GlgEI-V279S

254th National Meeting (2017)

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