Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability due to conformational flexibility. There is active research in developing these compounds for intracellular drug targeting but much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all conjugates were able to successfully target the islets of Langerhans. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Ease and efficiency make double-click helix stabilization a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation.

Alpha helix stabilization for improving the subcutaneous bioavailability of a helical peptide

253rd National Meeting (2017)

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