Taurine Boosts Cellular Uptake of Small D-Peptides for Enzyme-Instructed Intracellular Molecular Self-Assembly

Area of Science:

• Biochemistry
• Molecular Biology
• Biomedical Engineering

Background:

• D-peptides offer biostability for biomedical uses but exhibit poor cellular uptake due to proteolytic resistance and lack of transporter interaction.
• Enhancing D-peptide cellular entry is crucial for their effective application in intracellular therapies.

Purpose of the Study:

• To investigate the effect of taurine conjugation on D-peptide cellular uptake and intracellular accumulation.
• To elucidate the mechanism underlying taurine-enhanced D-peptide cellular entry.
• To explore the potential of taurine-conjugated D-peptides for intracellular molecular self-assembly.

Main Methods:

• Conjugation of taurine to small D-peptides.
• Quantification of cellular uptake using various concentrations of conjugated and unconjugated D-peptides in mammalian cells.
• Mechanism studies involving dynamin-dependent endocytosis and macropinocytosis inhibitors.
• Analysis of intracellular esterase activity and self-assembly of D-peptide derivatives.

Main Results:

• Taurine conjugation increased D-peptide cellular uptake by over 10-fold (from 118 μM to >1.6 mM).
• Taurine-D-peptide conjugates undergo intracellular esterase-triggered self-assembly, enhancing cellular accumulation.
• Cellular entry occurs via dynamin-dependent endocytosis and macropinocytosis, independent of taurine transporters.

Conclusions:

• Taurine conjugation is a potent strategy to significantly enhance D-peptide cellular uptake and intracellular accumulation.
• The enzyme-cleavable taurine motif facilitates intracellular self-assembly, offering novel therapeutic possibilities.
• This approach provides a biocompatible and stable method to improve the delivery of bioactive molecules for intracellular applications.