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https://hdl.handle.net/2440/139102
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Type: | Journal article |
Title: | Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen |
Author: | Horsfall, A.J. Chav, T. Pederick, J.L. Kikhtyak, Z. Vandborg, B.C. Kowalczyk, W. Scanlon, D.B. Tilley, W.D. Hickey, T.E. Abell, A.D. Bruning, J.B. |
Citation: | Journal of Medicinal Chemistry, 2023; 66(15):10354-10363 |
Publisher: | American Chemical Society |
Issue Date: | 2023 |
ISSN: | 0022-2623 1520-4804 |
Statement of Responsibility: | Aimee J. Horsfall, Theresa Chav, Jordan L. Pederick, Zoya Kikhtyak, Bethiney C. Vandborg, Wioleta Kowalczyk, Denis B. Scanlon, Wayne D. Tilley, Theresa E. Hickey, Andrew D. Abell, and John B. Bruning |
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 <i>N</i>-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. |
Keywords: | Cells; Fluorescence; Peptides and proteins; Permeability; Screening assays |
Description: | Published 10 August 2023 |
Rights: | © 2023 American Chemical Society |
DOI: | 10.1021/acs.jmedchem.3c00471 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1084416 http://purl.org/au-research/grants/arc/CE140100003 http://purl.org/au-research/grants/nhmrc/1130077 |
Published version: | http://dx.doi.org/10.1021/acs.jmedchem.3c00471 |
Appears in Collections: | Molecular and Biomedical Science publications |
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