Metal-mediated inhibition is a viable approach for inhibiting cellular methionine aminopeptidase.
Methionine aminopeptidase (MetAP) plays an essential role for cell survival. Hence, MetAP is a promising target for developing broad spectrum antibacterial agents. MetAP can be activated in vitro by a number of divalent metals, and X-ray structures show that the active site can accommodate two cations. Herein, we demonstrate bacterial growth inhibition by a compound that targets MetAP by recruitment of a third auxiliary metal. Contrary to previous beliefs, this shows that metal-mediated inhibition is a viable approach for discovering MetAP inhibitors that are effective for therapeutic application.
Chai
Sergio C
SC
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Ye
Qi-Zhuang
QZ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002413:Cations, Divalent / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008670:Metals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D063208:Methionyl Aminopeptidases; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002413:Cations, Divalent; D008670:Metals; D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases