Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins

J Biol Chem. 2012 Aug 3;287(32):26647-56. doi: 10.1074/jbc.M112.380782. Epub 2012 Jun 11.

Abstract

A series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Glutamic Acid / chemistry*
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Substrate Specificity

Substances

  • Dipeptides
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Glutamic Acid
  • Matrix Metalloproteinases

Associated data

  • PDB/3TS4
  • PDB/3TSK
  • PDB/3TT4
  • PDB/4EFS