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Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen.
Aimee J Horsfall1,2,3, Theresa Chav1,2,3, Jordan L Pederick1,4
1Institute of Photonics and Advanced Sensing (IPAS), The University of Adelaide, Adelaide, South Australia 5005, Australia.
Journal of Medicinal Chemistry
|July 25, 2023
Summary
Researchers developed a novel peptidomimetic targeting proliferating cell nuclear antigen (PCNA) for cancer therapy. This molecule, derived from p21, is cell-permeable and facilitates nuclear entry, offering a new strategy for anti-cancer drug development.
Area of Science:
- Molecular Biology
- Medicinal Chemistry
- Cancer Research
Background:
- Proliferating cell nuclear antigen (PCNA) is essential for DNA replication and repair.
- PCNA acts as a scaffold protein, interacting with numerous replication and repair factors.
- Targeting PCNA interactions is a potential strategy for inhibiting cancer cell proliferation.
Purpose of the Study:
- To design and synthesize a peptidomimetic agent that interacts with PCNA.
- To ensure the peptidomimetic is cell-permeable and can enter the cell nucleus.
- To explore the potential of PCNA-targeting peptidomimetics as anti-cancer agents or diagnostics.
Main Methods:
- Utilized a p21-derived peptide as a scaffold for peptidomimetic design.
- Conjugated a fluorescein tag and SV40 nuclear localization signal to the N-terminus of a p21 macrocycle derivative.
- Assessed cellular uptake and nuclear permeability of the synthesized peptidomimetic.
Main Results:
- Successfully produced a modular peptidomimetic capable of interacting with PCNA.
- The peptidomimetic demonstrated cellular and nuclear permeability.
- The fluorescein tag was found to be crucial for cellular uptake and nuclear entry.
Conclusions:
- Developed a novel, cell- and nuclear-permeable peptidomimetic targeting PCNA.
- This molecule represents a significant advancement in developing PCNA-targeting anti-cancer therapeutics.
- The findings support the potential utility of this peptidomimetic in cancer diagnostics and treatment.
