Abstract
AbstractStabilised peptides are now established as potential drug candidates to probe previously intractable molecular targets, such as protein‐protein interactions. Herein, we report the design and synthesis of eight short helical peptide analogues of the ubiquitin conjugating enzyme, E2‐25K, as potential antagonists of the interaction between E2‐25K and the Alzheimer's Disease (AD) associated ubiquitin mutant Ubb + 1. Biochemical evaluation revealed four putative antagonists of the Ubb + 1/E2‐25K interaction that reduced incorporation of Ubb + 1 into polyubiquitin chains in vitro, validating the potential of this approach as a therapeutic strategy.
Highlights
In Alzheimer's disease (AD) there is an urgent need for understanding disease pathomechanisms that underlie the accumulation of neurotoxic protein aggregates which represent the characteristic pathological hallmarks of the condition.[1]
A palette of peptides were successfully synthesised based on the α-9 sequence of E2-25K including the wild type sequence and eight stapled analogues with varying helicity values of 16%-91%
Modelling derived from the X-ray crystal structure of E2-25K in complex with Ubb + 1 was used in conjunction with biological data to offer some insight into the activities observed which is likely driven by hydrophobic interactions
Summary
In Alzheimer's disease (AD) there is an urgent need for understanding disease pathomechanisms that underlie the accumulation of neurotoxic protein aggregates which represent the characteristic pathological hallmarks of the condition.[1]. PPIs as potential drug targets have historically been difficult to target due to their large surface area which is generally devoid of pocket-like structures in which small molecules can bind.[13] Despite recent advances in identifying “hot-spots” that might serve as binding sites for small molecule inhibitors, using macromolecular constructs has proven effective in targeting various PPIs, and in particular short peptide mimics of the parent protein.[14] Pioneering work by both Grubbs and Verdine have shown that it is possible to inhibit PPIs through creating stabilised helical peptides capable of mimicking the α-helical interface at the PPI surface.[15,16,17,18] The use of stabilised peptides allows for maximum specific interactions with the target surface in the absence of any small molecule binding sites through combining the non-covalent forces and topological recognition of the parent sequence Based on this strong precedence, we elected to employ the technique of peptide stapling for our initial studies into inhibiting the E2-25K/Ubb + 1 PPI by creating a focused palette of short helical peptide analogues of the α-9 helix of E2-25K
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