An Immucillin‐Based Transition‐State‐Analogous Inhibitor of tRNA–Guanine Transglycosylase (TGT). Issue 20 (31st March 2016)

• Record Type: Journal Article
• Authors: Hohn, Christoph; Härtsch, Adrian; Ehrmann, Frederik Rainer; Pfaffeneder, Toni; Trapp, Nils; Dumele, Oliver; Klebe, Gerhard; Diederich, François
• Is Part Of: Chemistry. Volume 22:Issue 20(2016)
• Page Start: 6750
• Page End: 6754
• Publication Date: 2016-03-31
• Subjects: immucillin -- nucleosides -- shigellosis -- TGT -- transition-state analogues; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201600883
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : An immucillin derivative was designed as a putative transition‐state‐analogous inhibitor of the enzyme tRNA–guanine transglycosylase (TGT), a target of interest in the fight against shigellosis. The inhibitor was synthesized in a linear, 18‐step synthesis (see scheme) with an overall yield of 3 %. The predicted binding mode was confirmed by a co‐crystal structure analysis with Z. mobilis TGT.