Abstract
Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that has been shown to modify the properties of their monomeric states. Here, we identify a small molecule, called 10074-G5, capable of binding and sequestering the intrinsically disordered amyloid-β peptide (Aβ) in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterise this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. These results provide an illustration of the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behaviour for therapeutic purposes.
Teaser A small molecule binds to a disordered protein in its monomeric form, preventing its aggregation linked to Alzheimer’s disease.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
New experimental data added in this revision: 1.We now include new biolayer interferometry (BLI) data to characterise the binding between monomeric AB and the small molecule, 10074-G5 (Figure 1b). We also included an additional four-panel figure detailing the experimental setup (Figure S1a, b) and showing the specificity of the response that we observe (Figure S1c, d). Unlike the data in the previous submission, these experiments were performed with replicates, thus allowing us to include error bars. New analyses added in this revision: 2.We also include a new analysis of these BLI data to obtain more accurate kinetic parameters (Figure 1b). 3.We have now performed an analysis on the residue-specific differences in the conformational entropies between the apo and holo forms of the disordered peptide based on the metadynamic metainference simulations (Figure 3a). 4.We also now include kinetic fits to alternative models of aggregation inhibition, showing that the monomer sequestration model most effectively captures specific features of the observed data as compared to others (Figure S3d). Other changes: 5. C. elegans experiments have been removed.
