title: Inhibitors of Matriptase-2 Based on the Trypsin Inhibitor SFTI-1.
abstract: A series of 17 new analogues of trypsin inhibitor SFTI-1 were designed and synthesized to obtain matriptase-2 inhibitors. A number of the modified bicyclic peptides displayed much higher affinity towards matriptase-2 than towards the highly homologous matriptase-1. Replacement of Lys5 by Arg in the wild-type SFTI-1 led to an 11-fold increase in the matriptase-2 inhibitory activity. Replacement of Arg2 by its enantiomer (D-arginine) slightly lowered the inhibition of matriptase-2, but almost completely abolished the affinity towards matriptase-1, thus yielding the most selective matriptase-2 inhibitor. This is the first report describing inhibitors of the recently discovered matriptase-2 based on the SFTI-1 structure. The results showed that SFTI-1 is a promising scaffold for the design of potent and selective inhibitors of this enzyme.
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, University of Gdansk ul. Wita Stwosza 63, 80-308 Gdansk (Poland). agata.gitlin@phdstud.ug.edu.pl.
authors.forename: Agata
authors.initials: A
authors.lastname: Gitlin
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, University of Gdansk ul. Wita Stwosza 63, 80-308 Gdansk (Poland).
authors.forename: Dawid
authors.initials: D
authors.lastname: Dębowski
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, University of Gdansk ul. Wita Stwosza 63, 80-308 Gdansk (Poland).
authors.forename: Natalia
authors.initials: N
authors.lastname: Karna
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, University of Gdansk ul. Wita Stwosza 63, 80-308 Gdansk (Poland).
authors.forename: Anna
authors.initials: A
authors.lastname: Łęgowska
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, University of Gdansk ul. Wita Stwosza 63, 80-308 Gdansk (Poland).
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rolka
mesh_terms: D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; D014361:Trypsin Inhibitors; D012697:Serine Endopeptidases; C467801:matriptase 2
keywords: drug designenzymes; inhibitors; iron homeostasis; matriptases