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Updated: Jan 25, 2026
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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
2.8K
Understanding Cell Penetration of Cyclic Peptides
Patrick G Dougherty1, Ashweta Sahni1, Dehua Pei1
1Department of Chemistry and Biochemistry , The Ohio State University , 484 West 12th Avenue , Columbus , Ohio 43210 , United States.
Chemical Reviews
|May 16, 2019
Summary
Macrocyclic peptides can target previously undruggable proteins. However, most are cell-impermeable, limiting their use against intracellular targets. This review explores strategies to overcome this barrier for drug development.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Most disease-relevant human proteins are undruggable by conventional therapeutics.
- Macrocyclic peptides offer potential for targeting protein-protein interactions (PPIs) due to their size and binding capabilities.
- Current limitations include poor cell membrane permeability for most macrocyclic peptides, hindering intracellular applications.
Purpose of the Study:
- To review structural features affecting macrocyclic peptide cell permeability.
- To explore mechanisms and strategies for designing cell-permeable macrocyclic peptides.
- To discuss methods for quantifying macrocyclic peptide cell permeability.
Main Methods:
- Literature review of structural features and cell penetration mechanisms.
- Analysis of strategies for designing cell-permeable macrocyclic peptides.
- Examination of assay methods for quantifying cell permeability.
Main Results:
- Identified common structural characteristics that impede cell membrane passage.
- Highlighted unique features enabling cell entry via diffusion, endocytosis, or endosomal escape.
- Summarized current knowledge on molecular mechanisms of cell penetration.
Conclusions:
- Macrocyclic peptides show promise for targeting undruggable proteins, including intracellular PPIs.
- Overcoming cell permeability challenges is crucial for realizing their therapeutic potential.
- Further research into design strategies and assays is needed to advance macrocyclic peptide drug development.
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