Institute of Photonics and Advanced Sensing (IPAS), The University of Adelaide, Adelaide, South Australia 5005, Australia.
School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
J Med Chem. 2023 Aug 10;66(15):10354-10363. doi: 10.1021/acs.jmedchem.3c00471. Epub 2023 Jul 25.
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 -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.
人类增殖细胞核抗原（PCNA）是 DNA 复制和修复的关键介质，作为复制蛋白的对接平台。用肽模拟物破坏这些相互作用是限制癌细胞增殖的一种很有前途的方法。在这里，使用 p21 衍生肽作为起始支架来设计与 PCNA 相互作用且具有细胞和核通透性的模块肽模拟物。最终，设计出了一种符合这些标准的肽模拟物，它由荧光素标记物和 SV40 核定位信号连接到 p21 大环衍生物的 -末端。荧光素标记物的连接被发现直接影响肽模拟物的细胞摄取，而荧光素是核通透性所必需的。这项工作为开发针对 PCNA 的肽模拟物作为抗癌剂或癌症诊断试剂迈出了重要的一步。
