title: Inhibition of Mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives.
abstract: Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray crystal structure of human type 2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1a and MtMetAP1c in different metalloforms, inhibition of M. tuberculosis growth in replicating and non-replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M. tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lu
authors.forename: Xiu-Hua
authors.initials: XH
authors.lastname: Yuan
authors.forename: Hai
authors.initials: H
authors.lastname: Yuan
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Wang
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D018360:Crystallography, X-Ray; D006801:Humans; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D001381:Azepines; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases