Biology subjects

Dear, A.

Publications and source records attributed to Dear, A..

3 recordsLinked to original sources

bioRxiv2026

Errors in peptide synthesis are a source of discrepancies in Aβ42 studies

Amyloid-{beta}42 (A{beta}42) aggregation is highly sensitive to experimental conditions, making reproducibility a persistent challenge in Alzheimers disease research. Among the many variables that influence aggregation, the impact of peptide production remains poorly understood. Direct comparison of recombinant and chemically synthesised A{beta}42 prepared under carefully controlled conditions reveals that, despite following similar aggregation mechanism and forming the same predominant fibril structures, synthetic A{beta}42 aggregates more slowly and exhibits reduced seeding efficiency. Consequently, synthetic A{beta}42 produces fewer oligomeric species and displays lower cellular toxicity. Mass spectrometric analyses identify low-abundance sequence imperfections introduced during peptide synthesis as the origin of these differences. By linking synthesis-derived imperfections to variations in A{beta}42 behaviour, this work reveals a previously underappreciated source of discrepancies in amyloid studies. In addition, we provide a framework for evaluating the impact of sequence impurities on biophysical studies that are sensitive to peptide composition.

biochemistry↗

bioRxiv2025

Systematic molecular glue drug discovery with a high-throughput effector protein remodeling platform

Realising the promise of new medicines that operate through a targeted molecular glue-induced degradation mechanism requires systematic tools that can uncover the relevant principles of neomorphic protein-protein interactions. Whilst some monovalent glue degraders have been found through serendipity, the rules for small molecule attributes and the pairs or complexes of proteins that are amenable to drug-induced proximity control remain poorly articulated. Here we introduce a new approach to address this by using programmed libraries of intramolecularly edited proteins to expand protein surface landscapes and trigger new druggable interactions. We show that effector proteins, such as the E3 ligase Cereblon, can be engineered to provoke neomorphic activity by inducing the degradation of new client proteins and that these de novo interactions provide a blueprint from which new small molecule degraders can be built. As a demonstration of the approach, we use the platform to identify new non-IMiD molecular glue degraders of the oncology target GSPT1. SUMMARYO_LIMolecular glues are a highly important and promising new form of therapeutic agent, but rationalising their discovery has so far been impossible C_LIO_LIGlueSEEKER screening enables prospective monovalent drug discovery by using high-throughput deep mutational scanning to re-engineer the function of effector proteins like E3 ligases C_LIO_LIWe used this approach to enable the computational discovery of small molecule glues which degrade the oncology target GSPT1 and show how the technology can be used across new targets C_LI

bioengineering↗

bioRxiv2020

Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide

Oligomeric aggregates populated during the aggregation of the A{beta}42 peptide have been identified as potent cytotoxins linked to Alzheimers disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach combining theory, experiment, and simulation, we reveal in molecular detail the mechanisms of A{beta}42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we find that most A{beta}42 oligomers dissociate to their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar species. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.

biophysics↗