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Chembiochem ; 16(17): 2441-4, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26426719

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.


Subject(s)
Furin/antagonists & inhibitors , Peptides/chemistry , Amino Acid Sequence , Binding Sites , Drug Design , Furin/metabolism , Helianthus/metabolism , Kinetics , Molecular Dynamics Simulation , Peptides/chemical synthesis , Peptides/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Structure, Tertiary
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