Combinatorial tuning of peptidic drug candidates

The sunflower trypsin inhibitor-1 (SFTI-1) is a bicyclic tetradecapeptide and the starting point for structure-guided lead compound optimization (rational design) for new potent binders against the cancer-related protease matriptase-1. SFTI-1 comprises a backbone of 14 amino acids folded in a cyclic β-sheet that is threaded with an intramolecular disulfide bond. We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties towards matriptase-1. The most promising candidate had an improved activity of over 330-fold compared to the parent SFTI-1[1,14] molecule.

Fig.1: FITC labeled optimized SFTI variant bound to the surface of matriptase-1.
Fig.1: FITC labeled optimized SFTI variant bound to the surface of matriptase-1.

Related Publications

  • 1) Avrutina O, Fittler H, Glotzbach B, Kolmar H, Empting M. Between two worlds: a comparative study on in vitro and in silico inhibition of trypsin and matriptase by redox-stable SFTI-1 variants at near physio- logical pH. Organic biomolecular chemistry 2012; 10: 7753–7762.
  • 2) Fittler H, Avrutina O, Glotzbach B, Empting M, Kolmar H. Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization. Organic & biomolecular chemistry 2013; 11: 1848–1857.
  • 3) Fittler H, Avrutina O, Empting M, Kolmar H. Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor. Journal of Peptide Science 2014; 20: 415-420.