Targeting PCNA with peptide mimetics for therapeutic purposes

Abstract

Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad‐spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA‐interacting protein (PIP) box. There is large sequence diversity between high‐affinity PCNA binding partners, but with conservation of the binding structure - a well‐defined 3₁₀‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that stabilise the 3₁₀‐helix of PIP‐box partners are highlighted and related back to the canonical PIP‐box motif. High correlation with the canonical PIP‐box sequence does not directly afford high affinity. Instead, we summarise key interactions that stabilise the binding structure that leads to enhanced PCNA binding affinity. These interactions also implicate the “non‐conserved” residues within the PIP‐box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.