Journal
ACS CHEMICAL BIOLOGY
Volume 15, Issue 3, Pages 774-779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b01036
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Funding
- University of Pennsylvania
- National Institutes of Health
- NIH [UL1TR000003]
- National Science Foundation (NSF) [CHE-1150351]
- Chemistry Biology Interface Training Program [T32 GM071399]
- NSF [NSF CHE-1337449]
- MALDI MS (NSF) [MRI-0820996]
- HRMS (NIH) [RR-023444]
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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.
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