Open AccessStudies of Thioamide Effects on Serine Protease Activity Enable Two-Site Stabilization of Cancer Imaging Peptides
Author(s) -
Taylor M. Barrett,
Xing S. Chen,
Chunxiao Liu,
Sam Giannakoulias,
Hoang Phan,
Jieliang Wang,
E. Keith Keenan,
Richard J. Karpowicz,
E. James Petersson
Publication year - 2020
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.9b01036
Subject(s) - thioamide , proteases , chemistry , serine , proteolysis , protease , serine protease , biochemistry , peptide , context (archaeology) , serine proteinase inhibitors , stereochemistry , biology , enzyme , paleontology
Thioamide substitutions in peptides can be used as fluorescence quenchers in protease sensors and as stabilizing modifications of hormone analogs. To guide these applications in the context of serine proteases, we here examine the cleavage of several model substrates, scanning a thioamide between the P3 and P3' positions, and identify perturbing positions for thioamide substitution. While all serine proteases tested were affected by P1 thioamidation, certain proteases were also significantly affected by other thioamide positions. We demonstrate how these findings can be applied by harnessing the combined P3/P1 effect of a single thioamide on kallikrein proteolysis to protect two key positions in a neuropeptide Y-based imaging probe, increasing its serum half-life to >24 h while maintaining potency for binding to Y1 receptor expressing cells. Such stabilized peptide probes could find application in imaging cell populations in animal models or even in clinical applications such as fluorescence-guided surgery.