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J. Biol. Chem., Vol. 282, Issue 29, 20836-20846, July 20, 2007

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Inhibition of the Activation of Multiple Serine Proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing^*

Nathalie Méthot¹, Joel Rubin¹, Daniel Guay, Christian Beaulieu, Diane Ethier, T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival²

From the Department of Biochemistry and Molecular Biology, and Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Research Laboratories, 16711 Trans-Canada Highway, Kirkland Quebec H9H 3L1, Canada

Cathepsin C is a cysteine protease required for the activation of several pro-inflammatory serine proteases and, as such, is of interest as a therapeutic target. In cathepsin C-deficient mice and humans, the N-terminal processing and activation of neutrophil elastase, cathepsin G, and proteinase-3 is abolished and is accompanied by a reduction of protein levels. Pharmacologically, the consequence of cathepsin C inhibition on the activation of these serine proteases has not been described, due to the lack of stable and non-toxic inhibitors and the absence of appropriate experimental cell systems. Using novel reversible peptide nitrile inhibitors of cathepsin C, and cell-based assays with U937 and EcoM-G cells, we determined the effects of pharmacological inhibition of cathepsin C on serine protease activity. We show that indirect and complete inhibition of neutrophil elastase, cathepsin G, and proteinase-3 is achievable in intact cells with selective and non-cytotoxic cathepsin C inhibitors, at concentrations 10-fold higher than those required to inhibit purified cathepsin C. The concentration of inhibitor needed to block processing of these three serine proteases was similar, regardless of the cell system used. Importantly, cathepsin C inhibition must be sustained to maintain serine protease inhibition, because removal of the reversible inhibitors resulted in the activation of pro-enzymes in intact cells. These findings demonstrate that near complete inhibition of multiple serine proteases can be achieved with cathepsin C inhibitors and that cathepsin C inhibition represents a viable but challenging approach for the treatment of neutrophil-based inflammatory diseases.

Received for publication, March 27, 2007 , and in revised form, May 18, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1–S3.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy., Montreal H9H 2L1, Canada. Tel.: 514-428-3191; Fax: 514-428-4939; E-mail: david_percival{at}merck.com.

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