Modulating the selectivity of matriptase-2 inhibitors with unnatural amino acids.

Abstract

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.

• Authors: Catherine St-Georges, Antoine Désilets, François Béliveau, Mariana Ghinet, Sébastien P Dion, Éloic Colombo, Pierre-Luc Boudreault, Rafael J Najmanovich, Richard Leduc, Éric Marsault
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 129 Pg. 110-123 (Mar 31 2017) ISSN: 1768-3254 [Electronic] France
• PMID: 28219045 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amino Acids
• Enzyme Inhibitors
• Membrane Proteins
• Iron
• Serine Endopeptidases
• matriptase 2

Topics

• Amino Acids (chemistry)
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Homeostasis (drug effects)
• Humans
• Iron (metabolism)
• Iron Overload (drug therapy)
• Membrane Proteins (antagonists & inhibitors)
• Models, Molecular
• Sensitivity and Specificity
• Serine Endopeptidases
• Structure-Activity Relationship