Inhibition of Lethal Endotoxin Shock with an L-Pyridylalanine Containing Metalloproteinase Inhibitor Selected by High-Throughput Screening of a New Peptide Library

Title: Inhibition of Lethal Endotoxin Shock with an L-Pyridylalanine Containing Metalloproteinase Inhibitor Selected by High-Throughput Screening of a New Peptide Library

Volume: 9 Issue: 8

Author(s): Christiane Dillen, Pierre Fiten, Patrick Chaltin, Jialiang Hu, Veronique Dubois, Philippe E. Van den Steen and Ghislain Opdenakker

Affiliation:

Keywords: Matrix metalloproteinase, lipopolysaccharide, sepsis, inflammation, neutrophil, endotoxin

Abstract: Gelatinase B/MMP-9 fulfills crucial regulator or effector functions in disease states and may be pharmacologically targeted by specific inhibitors. The characteristics of cleavages of a natural gelatinase B substrate were simulated and amino acids with zinc-ion chelating side-groups were employed to design a library of peptide-based inhibitors. Here, we extend previous findings of combinatorial chemical synthesis and subsequent library deconvolution with a recently established high-throughput technology. This enabled us to study MMP inhibitors with two zinc-binding groups and to identify a new L-pyridylalanine-containing gelatinase B inhibitor. The peptide analog was found to inhibit, almost to the same degree, the neutrophil enzymes collagenase 2/ MMP-8 and MMP-9 and the monocytic tumor necrosis factor-β (TNF-β) converting enzyme (TACE/ADAM-17) in vitro and to protect mice against lethal endotoxinemia in vivo. These data illustrate the usefulness of the screening platform for protective inhibitor discovery and complement recent insights in the pathogenesis and treatment of shock syndromes.

Cite this article as:

Dillen Christiane, Fiten Pierre, Chaltin Patrick, Hu Jialiang, Dubois Veronique, Van den Steen E. Philippe and Opdenakker Ghislain, Inhibition of Lethal Endotoxin Shock with an L-Pyridylalanine Containing Metalloproteinase Inhibitor Selected by High-Throughput Screening of a New Peptide Library, Combinatorial Chemistry & High Throughput Screening 2006; 9 (8) . https://dx.doi.org/10.2174/138620706778249758