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Sugar Acetonides are a Superior Motif for Addressing the Large, Solvent‐Exposed Ribose‐33 Pocket of tRNA‐Guanine Transglycosylase
Author(s) -
Movsisyan Levon D.,
Schäfer Elisabeth,
Nguyen Andreas,
Ehrmann Frederik R.,
Schwab Anatol,
Rossolini Thomas,
Zimmerli Daniel,
Wagner Björn,
Daff Hamina,
Heine Andreas,
Klebe Gerhard,
Diederich François
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201801756
Subject(s) - guanine , druggability , biochemistry , acinetobacter baumannii , chemistry , ribose , sugar , biology , bacteria , stereochemistry , nucleotide , genetics , pseudomonas aeruginosa , gene , enzyme
The intestinal disease shigellosis caused by Shigella bacteria affects over 120 million people annually. There is an urgent demand for new drugs as resistance against common antibiotics emerges. Bacterial tRNA‐guanine transglycosylase (TGT) is a druggable target and controls the pathogenicity of Shigella flexneri . We report the synthesis of sugar‐functionalized lin ‐benzoguanines addressing the ribose‐33 pocket of TGT from Zymomonas mobilis . Ligand binding was analyzed by isothermal titration calorimetry and X‐ray crystallography. Pocket occupancy was optimized by variation of size and protective groups of the sugars. The participation of a polycyclic water‐cluster in the recognition of the sugar moiety was revealed. Acetonide‐protected ribo‐ and psicofuranosyl derivatives are highly potent, benefiting from structural rigidity, good solubility, and metabolic stability. We conclude that sugar acetonides have a significant but not yet broadly recognized value in drug development.