Design and chemical syntheses of potent matriptase-2 inhibitors based on trypsin inhibitor SFTI-1 isolated from sunflower seeds.

Abstract

Matriptase-2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase-2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI-1 designed to inhibit human matriptase-2. Influence of the modifications Gly1Lys, Ile10Arg, and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined. Selected peptides were further analyzed, together with previously reported peptides, for their inhibitory activity against related human proteases, that are, matriptase-1, plasmin, thrombin and trypsin. A highly potent inhibitor of matriptase-2, the bicycylic [Arg5 , Arg10 , His12 ]SFTI-1, with a Ki value of 15 nm was obtained.

• Authors: Agata Gitlin-Domagalska, Dawid Dębowski, Anna Łęgowska, Marit Stirnberg, Joanna Okońska, Michael Gütschow, Krzysztof Rolka
• Journal: Biopolymers (Biopolymers) Vol. 108 Issue 6 (Nov 2017) ISSN: 1097-0282 [Electronic] United States
• PMID: 28555756 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Membrane Proteins
• Peptides, Cyclic
• SFTI-1 peptide, sunflower
• Serine Proteinase Inhibitors
• Trypsin Inhibitors
• Serine Endopeptidases
• matriptase 2
• Trypsin
• Thrombin

Topics

• Amino Acid Sequence
• Drug Design
• Helianthus (chemistry, metabolism)
• Humans
• Kinetics
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Peptides, Cyclic (blood, chemistry)
• Protein Stability
• Seeds (chemistry, metabolism)
• Sequence Alignment
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (chemical synthesis, chemistry, metabolism)
• Thrombin (antagonists & inhibitors, metabolism)
• Trypsin (chemistry, metabolism)
• Trypsin Inhibitors (chemistry)