title: Inhibition of Kallikrein-Related Peptidases 7 and 5 by Grafting Serpin Reactive-Center Loop Sequences onto Sunflower Trypsin Inhibitor-1 (SFTI-1).
abstract: Serpin proteins irreversibly inhibit serine proteases, but only a small part of the serpin reactive-center loop (RCL) is responsible for the initial protein-protein interaction (PPI). To develop peptidic protease inhibitors, kallikrein-related peptidases 7 (KLK7) and 5 (KLK5) were chosen. Firstly, we demonstrated that short peptides derived from RCL sequences can be cleaved by KLK7 in a substrate-like manner. Next, these substrates were grafted onto the protease-binding loop of sunflower trypsin inhibitor-1 (SFTI-1). Peptides based on kallistatin, α1 -antichymotrypsin, and protein C inhibitor (PCI) inhibited KLK7 with Ki =0.4, 0.5, and 0.7 μm, respectively. In contrast, the trypsin-like KLK5 was only blocked by the peptide derived from PCI (Ki =0.6 μm). Thus, serpin function can be mimicked by introducing its PPI site into the rigid structure of the SFTI-1 scaffold. This approach might be applicable not only to KLKs but also to other serine protease members, thus opening up new therapeutic fields.
authors.affiliation: Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Brüderstrasse 34, 04103, Leipzig, Germany.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Jendrny
authors.affiliation: Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Brüderstrasse 34, 04103, Leipzig, Germany. beck-sickinger@uni-leipzig.de.
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015843:Serpins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C448501:SFTI-1 peptide, sunflower; D015842:Serine Proteinase Inhibitors; D015843:Serpins; C400147:KLK5 protein, human; C082472:KLK7 protein, human; D007610:Kallikreins
keywords: enzymes; inhibitors; peptides; reactive-center loops; serpins; sunflower trypsin inhibitor-1