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

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

  • Eur J Med Chem. 2017 Mar 31;129:110-123. doi: 10.1016/j.ejmech.2017.02.006.
Catherine St-Georges 1,  Antoine Désilets 1,  François Béliveau 1,  Mariana Ghinet 1,  Sébastien P Dion 1,  Éloic Colombo 1,  Pierre-Luc Boudreault 1,  Rafael J Najmanovich 2,  Richard Leduc 3,  Éric Marsault 4
Affiliations

Affiliations

  • 1 Department of Pharmacology-Physiology, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
  • 2 Department of Biochemistry, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
  • 3 Department of Pharmacology-Physiology, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada. Electronic address: Richard.Leduc@USherbrooke.ca.
  • 4 Department of Pharmacology-Physiology, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12(e) Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada. Electronic address: Eric.Marsault@usherbrooke.ca.
PMID: 28219045 DOI: 10.1016/j.ejmech.2017.02.006
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.

Keywords

Ketobenzothiazole; Matriptase; Matriptase-2; Peptidomimetics; Selectivity; Serine trap; Slow tight binding inhibitors; Type 2 transmembrane serine proteases.

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