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Hair dysplasias
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
Juan Ferrando, L. Alheli Niebla, Gerardo A. Moreno-Arias
In those cases associated with type 2 congenital pachionychia, a structural alteration of keratin 17 has been observed.28 Mutation of the ST14 gene (Cr 11q24.3-q.25) that encodes a protease (type II transmembrane serine protease matriptase) has been identified in cases of pili torti associated with hypotrichosis and ichthyosis.29 When associated with congenital hypotrichosis and juvenile macular dystrophy mutation has been identified in 16q22.1.30,31 Other mutations have also been identified in CDH3.
Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature
Published in Expert Opinion on Therapeutic Patents, 2020
Alexandre Murza, Sébastien P. Dion, Pierre-Luc Boudreault, Antoine Désilets, Richard Leduc, Éric Marsault
Matriptase has been associated for a long time with cancers. In particular, overexpression of matriptase or under-expression of its natural inhibitor Hepatocyte growth factor Activator Inhibitor 1 (HAI-1) has been reported in multiple cancers of epithelial tissues [89]. In an effort to discover a new treatment for carcinoma progression associated with matriptase [90], Lin and coworkers screened 69 small molecules tested at 75 µM for inhibitory activity against the recombinant enzyme (US6677377) [91]. Further Ki determination was reported on 15 compounds possessing >95% inhibition. Seven biphenyl derivatives bearing positively charged amidine groups separated by linkers of variable lengths emerged as the most interesting compounds in this series Figure 7A. Kis for matriptase range from 191 nM (13) to >10,000 nM while few compounds were also assessed for their ability to inhibit UPA and thrombin, with Kis in the µM range.
Aberrant regulation favours matriptase proteolysis in neoplastic B-cells that co-express HAI-2
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yi-Lin Chiu, Yi-Ying Wu, Robert B. Barndt, Yee Hui Yeo, Yu-Wen Lin, Hou-Ping Sytwo, Huan-Cheng Liu, Yuan Xu, Bailing Jia, Jehng-Kang Wang, Michael D. Johnson, Chen-Yong Lin
Matriptase is synthesised as a zymogen form, which possesses weak intrinsic activity like many other serine proteases. This matriptase zymogen intrinsic activity does not act on the same substrates as the mature activated enzyme, and it does not form stable complexes with protein protease inhibitors. This is because the substrate binding pocket has not assumed its mature (activated) conformation and so there are only low-affinity interactions between the protease zymogen and its substrates or protease inhibitors9,10. This intrinsic activity does, however, confer upon matriptase zymogen the ability to undergo autoactivation as the primary mechanism by which it acquires full enzymatic activity11, although the precise logistics of the activation mechanism, and more importantly how it is controlled, remain to be elucidated. Matriptase autoactivation can occur spontaneously and the rate of activation can be accelerated by various extracellular environmental factors such as a mildly acidic environment, reduced chloride concentrations, or a more oxidising redox environment12–14. Tumour microenvironments are commonly acidic and/or oxidative, under which conditions matriptase zymogen activation may be enhanced. Following matriptase zymogen activation, the newly formed active matriptase is either rapidly inhibited by the formation of high-affinity complexes with hepatocyte growth factor activator inhibitor (HAI)-1 or is shed from the cell surface15. The level of matriptase proteolytic activity in the pericellular environment is, therefore, determined by the dynamic balance between zymogen activation and the inhibition of the newly generated active matriptase.