Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors

Proteins. 2007 Feb 15;66(3):538-46. doi: 10.1002/prot.21207.

Abstract

In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole-diamines. Atomic-resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding.

MeSH terms

  • Aminopeptidases / chemistry
  • Aminopeptidases / isolation & purification
  • Bacteria / drug effects
  • Bacteria / enzymology*
  • Bacterial Proteins / pharmacology
  • Crystallization
  • Crystallography, X-Ray
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Methionyl Aminopeptidases
  • Models, Molecular
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • Quantum Theory

Substances

  • Bacterial Proteins
  • Protease Inhibitors
  • Aminopeptidases
  • Methionyl Aminopeptidases