Cyclic Peptides Binders for Lys63-Linked Ubiquitin Chains: Development and Applications
Ubiquitination is a complex post-translational modification (PTM) that plays a crucial role in different cellular pathways such as protein degradation and DNA repair. Ubiquitin can be conjugated to target proteins as a single moiety (mono-ubiquitination) or in the form of polyubiquitin chains. Different types of polyubiquitin chains, linked through a specific lysine residue of ubiquitin, serve as molecular signals for distinct cellular processes. For example, Lys63-linked chains play an important role in signalling for DNA-damage repair. Targeting a specific ubiquitin chain with the intent to develop a specific binder is a promising approach to modulate and target different various biological processes such as DNA repair.
In a previous study, we reported the first example of a Lys63-linked ubiquitin chain binder that interferes with protein-protein interaction and the subsequent biological activity. However, the cyclic peptide’s low aqueous solubility, cell permeability, and activity limit its use in advanced biological research and therapeutic applications.
In this seminar I will present on our study for structural alteration of the exocyclic and linker parts that resulted in a new derivative with considerably better cell activity, allowing us to study its mechanism of action in depth.