title: 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.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: St-Georges
authors.affiliation: 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.
authors.forename: Antoine
authors.initials: A
authors.lastname: Désilets
authors.affiliation: 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.
authors.forename: François
authors.initials: F
authors.lastname: Béliveau
authors.affiliation: 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.
authors.forename: Mariana
authors.initials: M
authors.lastname: Ghinet
authors.affiliation: 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.
authors.forename: Sébastien P
authors.initials: SP
authors.lastname: Dion
authors.affiliation: 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.
authors.forename: Éloic
authors.initials: É
authors.lastname: Colombo
authors.affiliation: 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.
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Boudreault
authors.affiliation: 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.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Najmanovich
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: 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.
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000188:drug therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C467801:matriptase 2
keywords: Ketobenzothiazole; Matriptase; Matriptase-2; Peptidomimetics; Selectivity; Serine trap; Slow tight binding inhibitors; Type 2 transmembrane serine proteases