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Published on: August 1, 2018
Modulating oxytocin activity and plasma stability by disulfide bond engineering.
Markus Muttenthaler1, Asa Andersson, Aline D de Araujo
1Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland.
Journal of Medicinal Chemistry
|December 2, 2010
Summary
Disulfide bond engineering in oxytocin analogues improved plasma stability 1.5-3 fold. Modified bridges like selenylsulfide retained significant receptor affinity and functional activity.
Area of Science:
- Peptide chemistry
- Medicinal chemistry
- Pharmacology
Background:
- Disulfide bonds are crucial for peptide structure and stability.
- Improving peptide metabolic half-life is essential for therapeutic applications.
- Oxytocin analogues are important for various physiological functions.
Purpose of the Study:
- To engineer oxytocin analogues with enhanced metabolic stability.
- To assess the impact of disulfide bond modifications on receptor binding and activity.
- To explore alternative bridges for improved pharmacokinetic properties.
Main Methods:
- Synthesis of eleven oxytocin analogues with modified disulfide bridges (thioether, selenylsulfide, diselenide, ditelluride).
- Assessment of plasma stability in human plasma.
- Evaluation of binding affinity (K(i)) and functional potency (EC₅₀) at the human oxytocin receptor.
Main Results:
- Selenylsulfide, diselenide, and ditelluride analogues retained considerable oxytocin receptor affinity and functional potency.
- Modified bridges showed 1.5-3 fold enhanced plasma stability compared to oxytocin.
- Shortening the disulfide bridge or using all-D-amino acids abolished activity.
Conclusions:
- Disulfide bond engineering offers a viable strategy to enhance oxytocin analogue stability.
- Specific modifications, such as selenylsulfide bridges, can maintain biological activity.
- These findings support the development of more stable peptide therapeutics.
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