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Uncovering supramolecular chirality codes for the design of tunable biomaterials.

Stephen J KlawaMichelle LeeKyle D RikerTengyue JianQunzhao WangYuan GaoMargaret L DalyShreeya BhongeW Seth ChildersTolulope O OmosunAnil K MehtaDavid G LynnRonit Freeman
Published in: Nature communications (2024)
In neurodegenerative diseases, polymorphism and supramolecular assembly of β-sheet amyloids are implicated in many different etiologies and may adopt either a left- or right-handed supramolecular chirality. Yet, the underlying principles of how sequence regulates supramolecular chirality remains unknown. Here, we characterize the sequence specificity of the central core of amyloid-β 42 and design derivatives which enable chirality inversion at biologically relevant temperatures. We further find that C-terminal modifications can tune the energy barrier of a left-to-right chiral inversion. Leveraging this design principle, we demonstrate how temperature-triggered chiral inversion of peptides hosting therapeutic payloads modulates the dosed release of an anticancer drug. These results suggest a generalizable approach for fine-tuning supramolecular chirality that can be applied in developing treatments to regulate amyloid morphology in neurodegeneration as well as in other disease states.
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