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Updated: Mar 7, 2026
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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
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Macrocyclic Peptides Containing an Imidazopyridinium (IP+) Unit Display Enhanced Passive Cell Permeability
Bo Li1, Joshua Parker1, Skyler Briggs2
1Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, 120 Scripps Way, Jupiter, Florida 33458, United States.
Journal of the American Chemical Society
|March 6, 2026
Summary
Imidazopyridinium (IP+) incorporation enhances macrocyclic peptide (MP) cell entry, enabling cytoplasmic access for targeting intracellular proteins. This strategy overcomes poor membrane permeability, leading to bioactive inhibitors for therapeutic development.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Delivery
Background:
- Macrocyclic peptides (MPs) show therapeutic promise for difficult protein targets.
- Poor passive membrane permeability limits MP application to intracellular targets.
- Previous work demonstrated imidazopyridinium (IP+) moiety enhances MP membrane permeability (PAMPA assay).
Purpose of the Study:
- To analyze the entry of IP+-containing MPs into living cells.
- To investigate the mechanism of IP+-MP cellular uptake.
- To evaluate the therapeutic potential of IP+-modified MPs for intracellular targets.
Main Methods:
- Chloroalkane penetration assay (CAPA) to measure cytoplasmic entry rates.
- Live-cell imaging, ATP-depletion experiments, and organelle colocalization studies.
- Assessment of IP+-MP activity against p53-MDM2 interaction and MCF-7 cell proliferation.
Main Results:
- IP+-containing MPs rapidly access the cytoplasm via passive diffusion, similar to small molecules.
- Uptake mechanism avoids endosomal entrapment and does not involve mitochondrial localization.
- An IP+-modified macrocyclic antagonist of p53-MDM2 becomes a bioactive inhibitor of MCF-7 proliferation.
- Enhanced permeability is achieved with IP+ either in the backbone or on a side chain.
Conclusions:
- Imidazopyridinium (IP+) incorporation is a viable strategy to enhance macrocyclic peptide (MP) cell permeability.
- IP+-MPs efficiently reach the cytoplasm through passive diffusion, overcoming a key limitation for intracellular drug development.
- This approach enables the creation of novel, bioactive MPs targeting intracellular proteins and diseases.
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