Glutamyl-gamma-boronate inhibitors of bacterial Glu-tRNA(Gln) amidotransferase

Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2001-09, Vol.11 (18), p.2561
Main Authors: Decicco, C P, Nelson, D J, Luo, Y, Shen, L, Horiuchi, K Y, Amsler, K M, Foster, L A, Spitz, S M, Merrill, J J, Sizemore, C F, Rogers, K C, Copeland, R A, Harpel, M R
Format: Article
Language:English
Subjects:
Anti-Infective Agents - chemistry
Anti-Infective Agents - pharmacology
Boronic Acids - chemistry
Boronic Acids - pharmacology
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Inhibitory Concentration 50
Microbial Sensitivity Tests
Nitrogenous Group Transferases - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.
ISSN:0960-894X
DOI:10.1016/S0960-894X(01)00499-1