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Published on: January 26, 2016
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Multi-site esterification: a tunable, reversible strategy to tailor therapeutic peptides for delivery.
Mark S Bannon1, Jeffrey F Ellena2, Aditi S Gourishankar1
1Department of Chemical Engineering, University of Virginia Charlottesville VA 22903 USA rl2qm@virginia.edu +1 434 243 3628.
Molecular Systems Design & Engineering
|September 16, 2024
Summary
Esterifying therapeutic peptides enhances cell membrane permeability. Modifying the number and position of esters on αCT11 impacts hydrophobicity and hydrolysis, enabling tunable peptide delivery.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Molecular Engineering
Background:
- Therapeutic peptides show promise but face delivery challenges due to low cell membrane permeability.
- Esterification of anionic peptides can improve hydrophobicity and cell internalization for intracellular targets.
Purpose of the Study:
- To investigate how the number and position of ester modifications on the therapeutic peptide αCT11 affect its hydrophobicity and hydrolysis.
- To provide molecular engineering insights for optimizing peptide esterification strategies.
Main Methods:
- Fischer esterification was used to install methyl esters onto the αCT11 peptide.
- Products were analyzed using 2D NMR, HPLC, and mass spectrometry to identify esterification sites and hydrophobicity.
- Hydrolysis rates and mechanisms, including aspartimide formation, were monitored.
Main Results:
- Five distinct esterified αCT11 products were isolated, with varying increases in hydrophobicity.
- Esterification at the C-terminal isoleucine yielded the greatest hydrophobicity increase.
- Hydrolysis stability varied, with C-terminal isoleucine esters being most stable, followed by glutamic acid, while aspartic acid esters hydrolyzed rapidly, forming transient aspartimides.
Conclusions:
- Multi-site esterification of therapeutic peptides is a tunable and reversible strategy for enhancing cell delivery.
- Understanding the impact of ester position on hydrophobicity and hydrolysis is crucial for designing effective peptide therapeutics.
- In vitro studies demonstrated improved cell migration with esterified αCT11, validating the approach.
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