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Rapid discovery of cyclic peptide protein aggregation inhibitors through continuous selection HTS data

ABSTRACT: We report a new platform for the rapid phenotypic selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in E. coli based on phage-assisted continuous evolution (PACE). Here, we developed a new PACE-compatible selection for protein aggregation inhibition and employed it to identify cyclic peptides that suppress amyloid-β42 (Aβ42) and human islet amyloid polypeptide (hIAPP) aggregation. Additionally, we integrated a negative selection that removes false positives and off-target hits, significantly improving cyclic peptide selectivity. We show that selected inhibitors are active when chemically re-synthesized in in vitro assays. Our platform provides a powerful new 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. Data deposited here are HTS data critical to the conclusions of this study.

ORGANISM(S): Inovirus M13

PROVIDER: GSE279094 | GEO | 2024/10/25

REPOSITORIES: GEO

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Project description:Martins2013 - True and apparent inhibition of amyloid fribril formation This model is described in the article: True and apparent inhibition of amyloid fibril formation. Martins PM. Prion 2013 Mar-Apr; 7(2): 136-139 Abstract: A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process. This model is hosted on BioModels Database and identified by: BIOMD0000000561. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Rapid discovery of cyclic peptide protein aggregation inhibitors through continuous selection HTS data

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