title: An Immucillin-Based Transition-State-Analogous Inhibitor of tRNA-Guanine Transglycosylase (TGT).
abstract: Shigellosis is one of the most severe diarrheal diseases worldwide without any efficient treatment so far. The enzyme tRNA-guanine transglycosylase (TGT) has been identified as a promising target for small-molecule drug design. Herein, we report a transition-state analogue, a small, immucillin-derived inhibitor, as a new lead structure with a novel mode of action. The complex inhibitor synthesis was accomplished in 18 steps with an overall yield of 3 %. A co-crystal structure of the inhibitor bound to Z. mobilis TGT confirmed the predicted conformation of the immucillin derivative in the enzyme active site.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hohn
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Härtsch
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Frederik Rainer
authors.initials: FR
authors.lastname: Ehrmann
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland.
authors.forename: Toni
authors.initials: T
authors.lastname: Pfaffeneder
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Trapp
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dumele
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany. klebe@mailer.uni-marburg.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, HCI, 8093, Zurich, Switzerland. diederich@org.chem.ethz.ch.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D017355:Zymomonas / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase
keywords: TGT; immucillin; nucleosides; shigellosis; transition-state analogues