A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity
- 29 June 2016
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 27 (7), 1663-1672
- https://doi.org/10.1021/acs.bioconjchem.6b00209
Abstract
Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, 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 (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. 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. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.Keywords
Funding Information
- National Cancer Institute (P30 CA046592)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK093766)
This publication has 79 references indexed in Scilit:
- Hydrophobic Fluorescent Probes Introduce Artifacts into Single Molecule Tracking Experiments Due to Non-Specific BindingPLOS ONE, 2013
- Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancerJournal of Translational Medicine, 2013
- Mechanistic Determinants of Biotherapeutics Absorption Following SC AdministrationThe AAPS Journal, 2012
- PET of Insulinoma Using 18F-FBEM-EM3106B, a New GLP-1 AnalogueMolecular Pharmaceutics, 2011
- Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analogProceedings of the National Academy of Sciences of the United States of America, 2011
- Rational Approach To Select Small Peptide Molecular Probes Labeled with Fluorescent Cyanine Dyes for in Vivo Optical ImagingBiochemistry, 2011
- Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki RatsJournal of Pharmacology and Experimental Therapeutics, 2010
- Targeting of α ν β 3 -Integrins Expressed on Tumor Tissue and Neovasculature Using Fluorescent Small Molecules and NanoparticlesNanomedicine, 2010
- Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeuticProceedings of the National Academy of Sciences, 2010
- Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)The Lancet, 2009