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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
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Chirality switching within an anionic cell-penetrating peptide inhibits translocation without affecting preferential
Tohru Yamada1, Sara Signorelli, Salvatore Cannistraro
1Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine , Chicago, Illinois 60612, United States.
Molecular Pharmaceutics
|December 6, 2014
Summary
Replacing even one l-amino acid with a d-amino acid in cell penetrating peptides (CPPs) can reduce their cellular uptake. This modification impacts peptide design for drug delivery.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Delivery Systems
Background:
- Cell-penetrating peptides (CPPs) facilitate cellular uptake of cargo.
- Amino acid chirality (l- vs. d-forms) influences peptide properties and function.
- Previous studies indicated multiple d-amino acid substitutions decrease CPP uptake.
Purpose of the Study:
- To investigate the effect of a single d-amino acid substitution on the uptake of an anionic CPP, p28.
- To determine if single d-substitution affects preferential uptake in cancer cells.
- To explore the relationship between d-substitution, chirality, secondary structure, and CPP uptake.
Main Methods:
- Synthesis and characterization of single d-amino acid substituted p28 analogues.
- Cellular uptake studies using cancer and normal cell lines.
- Analysis of peptide secondary structure (α-helix, β-sheet content).
Main Results:
- A single d-amino acid substitution decreased overall p28 uptake in both cancer and normal cells.
- Preferential uptake of p28 into cancer cells was maintained despite single d-substitution.
- Reduced uptake correlated with the position of d-substitution and its effect on chirality and secondary structure (α-helix/β-sheet ratio).
Conclusions:
- Single d-amino acid substitutions can modulate CPP uptake, affecting overall cellular entry.
- The impact of d-substitution depends on its position, chirality alteration, and secondary structure changes.
- Findings offer insights for designing d-substituted CPPs with altered membrane translocation properties for therapeutic applications.
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