Optimization of the cyclotide framework to improve cell penetration properties.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Delivery Systems

Background:

• Cell-penetrating peptides (CPPs) are promising for intracellular delivery but suffer from low serum stability.
• Cyclotides, plant-derived cyclic peptides, are highly stable and possess cell-penetrating properties, making them attractive drug design scaffolds.

Purpose of the Study:

• To enhance the cell internalization efficiency of cyclotides for broader application as drug delivery vectors.
• To engineer the MCoTI-II cyclotide scaffold to improve its cellular uptake while retaining its suitability for grafting bioactive sequences.

Main Methods:

• Modification of the MCoTI-II cyclotide scaffold.
• Assessment of the internalization properties of the modified MCoTI-II.
• Comparison of the internalization efficiency with the standard CPP, TAT peptide.

Main Results:

• Successfully modified MCoTI-II to improve its cellular internalization.
• The engineered MCoTI-II demonstrated internalization efficiency comparable to the TAT peptide.
• The modified cyclotide maintained its structural integrity as a scaffold for attaching bioactive sequences.

Conclusions:

• Engineered cyclotides offer a stable and efficient platform for intracellular drug delivery.
• Improved cyclotide internalization opens new possibilities for targeting intracellular proteins with peptide-based therapeutics.
• This work advances the application of cyclotides as versatile vectors in molecular design and drug development.