Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen

Human proliferating cell nuclearantigen (PCNA) is acritical mediatorof DNA replication and repair, acting as a docking platform for replicationproteins. Disrupting these interactions with a peptidomimetic agentpresents as a promising avenue to limit proliferation of cancerouscells. Here, a p21-derived peptide was employed as a starting scaffoldto design a modular peptidomimetic that interacts with PCNA and iscellular and nuclear permeable. Ultimately, a peptidomimetic was producedwhich met these criteria, consisting of a fluorescein tag and SV40nuclear localization signal conjugated to the N-terminusof a p21 macrocycle derivative. Attachment of the fluorescein tagwas found to directly affect cellular uptake of the peptidomimetic,with fluorescein being requisite for nuclear permeability. This workprovides an important step forward in the development of PCNA targetingpeptidomimetics for use as anti-cancer agents or as cancer diagnostics.