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|Title:||Rational design of a 310-helical PIP-box mimetic targeting PCNA - the human sliding clamp|
|Citation:||Chemistry - A European Journal, 2018; 24(44):11325-11331|
|Kate L. Wegener, Amy E. McGrath, Nicholas E. Dixon, Aaron J. Oakley, Denis B. Scanlon, Andrew D. Abell, John B. Bruning|
|Abstract:||The human sliding clamp (PCNA) controls access to DNA for many proteins involved in DNA replication and repair. Proteins are recruited to the PCNA surface by means of a short, conserved peptide motif known as the PCNA-interacting protein box (PIP-box). Inhibitors of these essential protein-protein interactions may be useful as cancer therapeutics by disrupting DNA replication and repair in these highly proliferative cells. PIP-box peptide mimetics have been identified as a potentially rapid route to potent PCNA inhibitors. Here we describe the rational design and synthesis of the first PCNA peptidomimetic ligands, based on the high affinity PIP-box sequence from the natural PCNA inhibitor p21. These mimetics incorporate covalent i,i+4 side-chain/side-chain lactam linkages of different lengths, designed to constrain the peptides into the 310-helical structure required for PCNA binding. NMR studies confirmed that while the unmodified p21 peptide had little defined structure in solution, mimetic ACR2 pre-organised into 310-helical structure prior to interaction with PCNA. ACR2 displayed higher affinity binding than most known PIP-box peptides, and retains the native PCNA binding mode, as observed in the co-crystal structure of ACR2 bound to PCNA. This study offers a promising new strategy for PCNA inhibitor design for use as anti-cancer therapeutics.|
|Keywords:||PCNA; replication inhibitor; sliding clamp; peptide mimetic; lactam|
|Rights:||© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim|
|Appears in Collections:||IPAS publications|
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