Title: Inhibition of lethal endotoxin shock with an L-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library
Authors: Hu, Jialiang
Dubois, Véronique
Chaltin, Patrick
Fiten, Pierre
Dillen, Christiane
Van den Steen, Philippe
Opdenakker, Ghislain # ×
Issue Date: Sep-2006
Publisher: Bentham Science Publishers
Series Title: Combinatorial Chemistry & High Throughput Screening vol:9 issue:8 pages:599-611
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-alpha (TNF-alpha) 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.
ISSN: 1386-2073
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular Immunology (Rega Institute)
Intellectual Property
Laboratory of Immunobiology (Rega Institute)
× corresponding author
# (joint) last author

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