Glycan shields for penetrating peptides

Area of Science:

• Bioconjugation Chemistry
• Peptide Therapeutics
• Glycobiology

Background:

• Cell penetrating peptides (CPPs) are vital for drug delivery but often exhibit toxicity.
• Glycosylation is explored to modify peptide properties, but efficient synthesis and biological impact remain challenging.

Purpose of the Study:

• To develop and evaluate novel glycan shields for CPPs.
• To investigate the effect of glycosylation on CPP cellular uptake, toxicity, and biodistribution.

Main Methods:

• Synthesis of glycosylated peptides using a novel benzyl alkoxyamine connector and oxyme bond formation.
• Biological evaluation of CPPs with varying saccharide substitutions for cellular uptake, toxicity, and in vivo biodistribution.

Main Results:

• A straightforward method for preparing highly glycosylated CPPs was established.
• Saccharide substitution (4-6 units) did not impede cellular uptake efficiency.
• Glycan shielding significantly improved the toxicity profile of CPPs.
• Glucose-substituted CPPs demonstrated excellent in vitro uptake and intracellular localization.
• Optimal glucose shielding resulted in superior in vivo biodistribution.

Conclusions:

• Glycan shields represent a promising strategy to enhance the safety of CPPs.
• The developed synthetic approach allows for efficient preparation of functionalized CPPs.
• Glucose emerges as a key glycan for optimizing CPP performance in biological systems.