Definition of peptide inhibitors from a synthetic peptide library by targeting gelatinase B/matrix metalloproteinase-9 (MMP-9) and TNF-α converting enzyme (TACE/ADAM-17)

J Enzyme Inhib Med Chem. 2012 Aug;27(4):533-40. doi: 10.3109/14756366.2011.599323. Epub 2011 Aug 10.

Abstract

Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a regulatory and effector metalloproteinase in inflammation. TNF-α is an important proinflammatory cytokine and is released by the action of a Zn(2+)-containing converting enzyme (TACE/ADAM-17). Both metallo-enzymes play important roles during the development of shock syndromes. Combinatorial chemical synthesis and subsequent library deconvolution were previously used to define a peptide inhibitor (Regasepin1) acting, almost to the same degree, on neutrophil collagenase/MMP-8 and MMP-9 in vitro, and protecting mice against lethal endotoxinemia in vivo. We have now extended this approach by incorporating D-form amino acids and residues preferred by TACE. A new peptide library was designed and synthesized, and by deconvolution new peptide inhibitors were defined. These included a TACE-specific inhibitor, an MMP-9- specific inhibitor, and inhibitors for both enzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Peptide Library*
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Peptide Library
  • Peptides
  • Recombinant Proteins
  • ADAM Proteins
  • Matrix Metalloproteinase 9
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse