Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors |
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Authors: | Heiko Fittler Alexander Depp Dr Olga Avrutina Dr Sven O Dahms Dr Manuel E Than Dr Martin Empting Prof?Dr Harald Kolmar |
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Affiliation: | 1. Clemens-Sch?pf-Institut für organische und Biochemie, Technische Universit?t Darmstadt, Darmstadt, Germany;2. Leibniz Institute for Age Research–Fritz Lipmann Institute (FLI), Jena, Germany;3. Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany |
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Abstract: | We report the engineering of the monocyclic sunflower trypsin inhibitor (SFTI‐11,14]) 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. |
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Keywords: | Bowman-Birk inhibitor furin protein engineering rational design SFTI-1 structure– activity relationships |
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