Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor.
Sunflower trypsin inhibitor-1 (SFTI-1), a bicyclic tetradecapeptide, has become a versatile tool as a scaffold for the development of the inhibitors of therapeutically relevant serine proteases, among them matriptase and kallikreins. Herein, we report the rational design of potent monocyclic and bicyclic inhibitors of human matriptase-1. We found that the presence of positive charge and lack of bulky residues at the peptide N-terminus is required for the maintenance of inhibitory activity. Replacement of the N-terminal glycine residue by lysine allowed for the chemical conjugation with a fluorophor via the ε-amino group without significant loss of inhibitory activity. Head-to-tail and side-chain-to-tail cyclization resulted in potent inhibitors with comparable activities against matriptase-1. The most potent synthetic bicyclic inhibitor found in this study (Ki  = 2.6 nM at pH 7.6) is a truncated version of SFTI-1 (cyclo-KRCTKSIPPRCH) lacking a C-terminal proline and aspartate residue. It combines an internal disulfide bond with a peptide macrocycle that is formed through side-chain-to-tail cyclization of the ε-amino group of an N-terminal lysine and a C-terminal proline.
Clemens-Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 4, 64287, Darmstadt, Germany.
Heiko
H
Fittler
Olga
O
Avrutina
Martin
M
Empting
Harald
H
Kolmar
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485596:ST14 protein, human
Bowman-Birk inhibitors; SFTI-1; human matriptase-1; rational design