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Molecular Pharmacology

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Research ArticleArticle

In Vivo Inhibition of Serine Protease Processing Requires a High Fractional Inhibition of Cathepsin C

Nathalie Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau and M. David Percival
Molecular Pharmacology June 2008, 73 (6) 1857-1865; DOI: https://doi.org/10.1124/mol.108.045682
Nathalie Méthot
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Daniel Guay
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Joel Rubin
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Diane Ethier
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Karen Ortega
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Simon Wong
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Denis Normandin
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Christian Beaulieu
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T. Jagadeeswar Reddy
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Denis Riendeau
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M. David Percival
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Abstract

Inhibition of cathepsin C, a dipeptidyl peptidase that activates many serine proteases, represents an attractive therapeutic strategy for inflammatory diseases with a high neutrophil burden. We recently showed the feasibility of blocking the activation of neutrophil elastase, cathepsin G, and proteinase-3 with a single cathepsin C selective inhibitor in cultured cells. Here we measured the fractional inhibition of cathepsin C that is required for blockade of downstream serine protease processing, in cell-based assays and in vivo. Using a radiolabeled active site probe and U937 cells, a 50% reduction of cathepsin G processing required ∼50% of cathepsin C active sites to be occupied by an inhibitor. In EcoM-G cells, inhibition of 50% of neutrophil elastase activity required ∼80% occupancy. Both of these serine proteases were fully inhibited at full cathepsin C active site occupancy, whereas granzyme B processing in TALL-104 cells was partially inhibited, despite complete occupancy. In vivo, leukocytes from cathepsin C+/- mice exhibited comparable levels of neutrophil elastase activity to wild-type animals, even though their cathepsin C activity was reduced by half. The long-term administration of a cathepsin C inhibitor to rats, at doses that resulted in the nearly complete blockade of cathepsin C active sites in bone marrow, caused significant reductions of neutrophil elastase, cathepsin G and proteinase-3 activities. Our results demonstrate that the inhibition of cathepsin C leads to a decrease of activity of multiple serine proteases involved in inflammation but also suggest that high fractional inhibition is necessary to reach therapeutically significant effects.

Footnotes

  • ABBREVIATIONS: PLS, Papillon-Lefèvre syndrome; CG, cathepsin G; NE, neutrophil elastase; Pr-3, proteinase-3; gB, granzyme B; GF-DMK, Gly-Phe-DMK; DMK, diazomethyl ketone; M867, (3S)-3-({(2S)-2-[5-tert-butyl-3-{[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino}-2-oxopyrazin-1(2H)-yl]butanoyl}amino)-5-[methyl(pentyl)amino]-4-oxopentanoic acid; L-694,458, N-(1-(1,3-benzodioxol-5-yl)butyl)-3,3-diethyl-2-(4-((4-methyl-1-piperazinyl)carbonyl)phenoxy)-4-oxo-1-azetidinecarboxamide; AMC, aminomethyl coumarin; PBS, phosphate-buffered saline; NP40, nonidet P40; IL, interleukin; FBS, fetal bovine serum; PAGE, polyacrylamide gel electrophoresis; IEPD, Ile-Glu-Pro-Asp; EOA, enzyme occupancy assay; MPO, myeloperoxidase; MES, 2-(N-morpholino)ethanesulfonic acid.

    • Received January 25, 2008.
    • Accepted February 15, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

In Vivo Inhibition of Serine Protease Processing Requires a High Fractional Inhibition of Cathepsin C

Nathalie Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau and M. David Percival
Molecular Pharmacology June 1, 2008, 73 (6) 1857-1865; DOI: https://doi.org/10.1124/mol.108.045682

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Research ArticleArticle

In Vivo Inhibition of Serine Protease Processing Requires a High Fractional Inhibition of Cathepsin C

Nathalie Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau and M. David Percival
Molecular Pharmacology June 1, 2008, 73 (6) 1857-1865; DOI: https://doi.org/10.1124/mol.108.045682
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