Inhibition of lethal endotoxin shock with an L-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library.
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.
Hu
Jialiang
J
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Dubois
Véronique
V
Chaltin
Patrick
P
Fiten
Pierre
P
Dillen
Christiane
C
Van den Steen
Philippe E
PE
Opdenakker
Ghislain
G
D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009504:Neutrophils / Q000201:enzymology; D019151:Peptide Library; D010455:Peptides; D012772:Shock, Septic / Q000188:drug therapy* / Q000517:prevention & control; D015032:Zinc
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019151:Peptide Library; D010455:Peptides; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D015032:Zinc; D000409:Alanine