Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor

作者：Fittler Heiko; Avrutina Olga; Empting Martin; Kolmar Harald^*

来源：Journal of Peptide Science, 2014, 20(6): 415-420.

DOI：10.1002/psc.2629

• rational design
• SFTI-1
• human matriptase-1
• Bowman-Birk inhibitors

Sunflower trypsin inhibitor-1 (SFTI-1), a bicyclic tetradecapeptide, has become a versatile tool as a scaffold for the development of the inhibitors of therapeutically relevant serine proteases, among them matriptase and kallikreins. Herein, we report the rational design of potent monocyclic and bicyclic inhibitors of human matriptase-1. We found that the presence of positive charge and lack of bulky residues at the peptide N-terminus is required for the maintenance of inhibitory activity. Replacement of the N-terminal glycine residue by lysine allowed for the chemical conjugation with a fluorophor via the epsilon-amino group without significant loss of inhibitory activity. Head-to-tail and side-chain-to-tail cyclization resulted in potent inhibitors with comparable activities against matriptase-1. The most potent synthetic bicyclic inhibitor found in this study (K-i=2.6nM at pH 7.6) is a truncated version of SFTI-1 (cyclo-KRCTKSIPPRCH) lacking a C-terminal proline and aspartate residue. It combines an internal disulfide bond with a peptide macrocycle that is formed through side-chain-to-tail cyclization of the epsilon-amino group of an N-terminal lysine and a C-terminal proline.

• 出版日期2014-6