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Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors
Author(s) -
Fittler Heiko,
Depp Alexander,
Avrutina Olga,
Dahms Sven O.,
Than Manuel E.,
Empting Martin,
Kolmar Harald
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500447
Subject(s) - furin , serine protease , trypsin , proteases , protease , biochemistry , chemistry , protein engineering , peptide , serine , enzyme
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 n m , the engineered peptide H‐KRCKKSIPPICF‐NH 2 is a promising compound for further development of furin inhibitors aimed at controlling the activity of this protease in vitro and in vivo.