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Chembiochem. 2015 Nov;16(17):2441-4. doi: 10.1002/cbic.201500447. Epub 2015 Oct 19.

Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors.

Author information

1
Clemens-Schöpf-Institut für organische und Biochemie, Technische Universität Darmstadt, Alarich-Weiss Strasse 4, 64287, Darmstadt, Germany.
2
Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745, Jena, Germany.
3
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123, Saarbrücken, Germany.
4
Clemens-Schöpf-Institut für organische und Biochemie, Technische Universität Darmstadt, Alarich-Weiss Strasse 4, 64287, Darmstadt, Germany. kolmar@biochemie-tud.de.

Abstract

We report the engineering of the monocyclic sunflower trypsin inhibitor (SFTI-1[1,14]) into a potent furin inhibitor. In a rational approach, we converted the native scaffold of this trypsin-like serine protease inhibitor into a subtilisin-like one by substitutions in the canonical and, particularly, in the substrate-binding loop. Although the substrate sequence for furin is Arg-X-Arg/Lys-Arg↓, the most potent inhibitor had a lysine at position P1. C-terminally truncated versions demonstrated the strongest activity, thus suggesting a lack of interaction between this motif and the surface of furin. This observation was further supported by molecular modeling. With an inhibition constant of 0.49 nm, the engineered peptide H-KRCKKSIPPICF-NH2 is a promising compound for further development of furin inhibitors aimed at controlling the activity of this protease in vitro and in vivo.

KEYWORDS:

Bowman-Birk inhibitor; SFTI-1; furin; protein engineering; rational design; structure-activity relationships

PMID:
26426719
DOI:
10.1002/cbic.201500447
[Indexed for MEDLINE]

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