Inhibitors of cathepsin C (dipeptidyl peptidase I)

Lainé, Dramane I.; Busch-Petersen, Jakob

doi:10.1517/13543771003657172

Cited by 39 publications

(86 citation statements)

References 31 publications

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“…Most of the reported inhibitors are based on the preferred dipeptide substrates bearing either irreversible or reversible electrophilic groups. In the past years dipeptidyl nitriles have attracted great attention due to their strong inhibitory activity against human CatC (23,24). Inactivation of CatC in the bone marrow of rats by treating them with a reversible cyclopropyl nitrile inhibitor for 2 weeks at doses that resulted in the nearly complete inhibition of CatC only partially prevents activation of NSPs (25).…”

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confidence: 99%

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Hamon

Łęgowska

Hervé

et al. 2016

Journal of Biological Chemistry

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The cysteine protease cathepsin C (CatC) activates granuleassociated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysisdriven chronic inflammatory diseases, but its complete inhibition is elusive in vivo. Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ϳ80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.

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Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Hamon

Łęgowska

Hervé

et al. 2016

Journal of Biological Chemistry

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“…17 A catalytic ion pair near the scissile peptide bond is formed by the Cys234 and His381 residues. 18 The S1 site is not a well-defined pocket but rather a surface located near the solvent surface. The S2 pocket is deep and hydrophobic and contains a chloride ion and two solvent molecules at the bottom.…”

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Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C

Lainé

Palovich

McCleland

et al. 2010

ACS Med. Chem. Lett.

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“…It is involved in the maturation of regulatory peptides such as the activation of peptide hormones and neuropeptides, which support its role in bioactive peptide generation, which in turn is of great therapeutic potential. It also plays a key role in the pathobiology of sepsis, abdominal aortic aneurysm, rheumatoid arthritis and other inflammatory disorders such as lung fibrosis, cystic fibrosis and chronic obstructive pulmonary disease [11][12][13][14][15].…”

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confidence: 99%