Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen
Date
2023
Authors
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.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Medicinal Chemistry, 2023; 66(15):10354-10363
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
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Published 10 August 2023
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Rights
© 2023 American Chemical Society