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.
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