Studies of Thioamide Effects on Serine Protease Activity Enable Two-Site Stabilization of Cancer Imaging Peptides
2020
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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