Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 70, Issue -, Pages 661-668Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.10.040
Keywords
Netherton syndrome; Skin diseases; Kallikreins; Small organic molecules; Virtual screening; In vitro screening; Reversible inhibitors
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Funding
- Institut National pour la Recherche Medicale (INSERM)
- Universite Pierre et Marie Curie (UPMC)
- Agence Nationale de Recherche (grant ANR-GENOPAT)
- French Ministry of Research and Education
- Agence Nationale de Recherche
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Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrome phenotype. The efficacy and mechanism of inhibition of the identified new families of organic compounds were analyzed not only for hK5 but also on other proteases implicated in the cascades (hK7, hK14 and matriptase). These inhibitors are nontoxic on healthy human keratinocytes and are structurally different from traditional serine protease inhibitors validating their potential utility as initial hits to control proteolytic disorders observed in dermatological pathologies such as Netherton syndrome. (C) 2013 Elsevier Masson SAS. All rights reserved.
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