Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 129, Issue -, Pages 110-123Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.02.006
Keywords
Type 2 transmembrane serine proteases; Matriptase-2; Matriptase; Slow tight binding inhibitors; Selectivity; Peptidomimetics; Ketobenzothiazole; Serine trap
Categories
Funding
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Canadian Foundation for Innovation
Ask authors/readers for more resources
Matriptase-2, a type II transmembrane serine protease (TTSP), is expressed in the liver and regulates iron homeostasis via the cleavage of hemojuvelin. Matriptase-2 emerges as an attractive target for the treatment of conditions associated with iron overload, such as hemochromatosis or beta-thalassemia. Starting from the crystal structure of its closest homolog matriptase, we constructed a homology model of matriptase-2 in order to further optimize the selectivity of serine trap peptidomimetic inhibitors for matriptase-2 vs matriptase. Careful modifications of the P4, P3 and P2 positions with the help of unnatural amino acids led to a thorough understanding of Structure-Activity Relationship and a > 60-fold increase in selectivity for matriptase-2 vs matriptase. Additionally, the introduction of unnatural amino acids led to significant increases in plasma stability. Such compounds represent useful pharmacological tools to test matriptase-2 inhibition in a context of iron overload. (C) 2017 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available