Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors. Issue 17 (19th October 2015)

• Record Type: Journal Article
• Authors: Fittler, Heiko; Depp, Alexander; Avrutina, Olga; Dahms, Sven O.; Than, Manuel E.; Empting, Martin; Kolmar, Harald
• Is Part Of: Chembiochem. Volume 16:Issue 17(2015)
• Page Start: 2441
• Page End: 2444
• Publication Date: 2015-10-19
• Subjects: Bowman-Birk inhibitor -- furin -- protein engineering -- rational design -- SFTI-1 -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500447
• Languages: English
• ISSNs: 1439-4227

Abstract

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. Abstract : Potent inhibitors of therapeutically relevant serine protease furin were rationally designed on the constrained scaffold of the sunflower trypsin inhibitor‐1 (SFTI‐1[1, 14]). We transformed the trypsin‐like inhibitor into the subtilisin‐like inhibitor. The best obtained candidate, truncated at the C terminus by two amino acids, exhibited a K i of 0.49 nm .