DprE1--from the discovery to the promising tuberculosis drug target.
Several groups working in the field of the development of new antituberculosis drugs have recently reported active compounds targeting mycobacterial enzyme DprE1. Along with its counterpart, DprE2, it catalyses a unique epimerization reaction resulting in the synthesis of decaprenylphosphoryl arabinose, the single donor of arabinosyl residues for the build-up of arabinans, fundamental components of the mycobacterial cell wall. This review presents the historical background leading to the discovery of DprE1, focusing on the biochemical and structural characterization of this important emerging target and introducing the molecules acting on DprE1 including the development of the most successful series--the benzothiazinones, currently in late pre-clinical development, which turned to be suicide inhibitors of DprE1.
Katarína
K
Mikusová
Vadim
V
Makarov
Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina, 84215 Bratislava, Slovakia. mikusova@fns.uniba.sk.
João
J
Neres
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011134:Polysaccharides / Q000096:biosynthesis; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011134:Polysaccharides; D013843:Thiazines; C030080:araban; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis