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Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection
Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection
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Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection
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Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection
Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection
Journal Article

Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection

2025
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Overview
Protein aggregates are associated with numerous diseases. Here we report a platform for the rapid phenotypic selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli based on phage-assisted continuous evolution (PACE). We developed a new PACE-compatible selection for protein aggregation inhibition and used it to identify cyclic peptides that suppress amyloid-β42 and human islet amyloid polypeptide aggregation. Additionally, we integrated a negative selection that removes false positives and off-target hits, greatly improving cyclic peptide selectivity. We show that selected inhibitors are active when chemically resynthesized in in vitro assays. Our platform provides a powerful approach for the rapid discovery of cyclic peptide inhibitors of protein aggregation and may serve as the basis for the future evolution of cyclic peptides with a broad spectrum of inhibitory activities. A platform for the continuous selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli was developed. This platform was used to discover cyclic peptides that suppress aggregation of amyloid-β42 and human islet amyloid polypeptide.