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Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides
Thomas Vorherr1, Ian Lewis1, Joerg Berghausen1
1Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
International Journal of Peptide Research and Therapeutics
|March 13, 2018
Summary
Minor modifications to cyclic peptide side chains significantly influence both cell permeability and liver metabolism, aiding oral drug discovery. These findings are crucial for developing orally bioavailable peptide therapeutics.
Area of Science:
- Medicinal Chemistry
- Pharmacokinetics
- Drug Discovery
Background:
- Cyclic peptides offer therapeutic potential but face challenges in oral bioavailability and cell permeability.
- Strategies like N-methylation and polarity masking aim to improve peptide drug properties.
- Understanding how structural modifications affect both absorption and metabolism is critical.
Purpose of the Study:
- To investigate the impact of shielding strategies on peptide permeability.
- To analyze the liver metabolism of modified peptides.
- To correlate structural changes with pharmacokinetic properties.
Main Methods:
- Comparison of peptide concentrations in portal versus jugular veins in rats.
- Assessment of permeability across biological barriers.
- Metabolic stability studies in liver models.
Main Results:
- Minor alterations in a specific side chain profoundly affected peptide permeability.
- The same side chain modifications influenced liver metabolism.
- A direct link was observed between shielding, permeability, and metabolic fate.
Conclusions:
- Side chain shielding is a key factor influencing both the permeability and liver metabolism of cyclic peptides.
- These findings provide valuable insights for designing orally bioavailable peptide drugs.
- Further research into structure-metabolism relationships can optimize peptide drug development.
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