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Published on: December 19, 2020
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.
Abstract:
Human proliferating cell nuclear antigen (PCNA) is a critical mediator of DNA replication and repair, acting as a docking platform for replication proteins. Disrupting these interactions with a peptidomimetic agent presents as a promising avenue to limit proliferation of cancerous cells. Here, a p21-derived peptide was employed as a starting scaffold to design a modular peptidomimetic that interacts with PCNA and is cellular and nuclear permeable. Ultimately, a peptidomimetic was produced which met these criteria, consisting of a fluorescein tag and SV40 nuclear localization signal conjugated to the N-terminus of a p21 macrocycle derivative. Attachment of the fluorescein tag was found to directly affect cellular uptake of the peptidomimetic, with fluorescein being requisite for nuclear permeability. This work provides an important step forward in the development of PCNA targeting peptidomimetics for use as anti-cancer agents or as cancer diagnostics.
Insights
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.
