Targeting of protein aggregates is technologically challenging. We developed a phage-assisted continuous evolution platform for rapid selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli. This strategy enabled discovery of cyclic peptides that suppress the aggregation of two clinically relevant proteins, amyloid-β42 (Aβ42) and human islet amyloid polypeptide (hIAPP).
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References
Sohrabi, C., Foster, A. & Tavassoli, A. Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery. Nat. Rev. Chem. 4, 90–101 (2020). A review that presents methods for high-throughput screening and selection of genetically encoded cyclic peptide libraries.
Armiento, V., Spanopoulou, A. & Kapurniotu, A. Peptide-based molecular strategies to interfere with protein misfolding, aggregation, and cell degeneration. Angew. Chem. Int. Ed. 59, 3372–3384 (2019). A review that presents molecular concepts behind amyloid formation and peptide aggregation inhibitor design.
Delivoria, D. C. et al. Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation. Sci. Adv. 5, eaax5108 (2019). This paper reports identification of head-to-tail cyclic peptide inhibitors of Aβ42 aggregation using high-throughput screening with an Aβ42–GFP reporter in E. coli and fluorescence-activated cell sorting.
Miller, S. M., Wang, T. & Liu, D. R. Phage-assisted continuous and non-continuous evolution. Nat. Protoc. 15, 4101–4127 (2020). This protocol provides detailed instructions on evolving proteins using PACE and a non-continuous variant.
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This is a summary of: Yang, L. et al. Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection. Nat. Chem. Biol. https://doi.org/10.1038/s41589-024-01823-x (2025).
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Continuous selection in E. coli to identify cyclic peptide inhibitors of protein aggregation. Nat Chem Biol 21, 472–473 (2025). https://doi.org/10.1038/s41589-024-01824-w
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DOI: https://doi.org/10.1038/s41589-024-01824-w
