Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation.

ABSTRACT: Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer's and Parkinson's diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer's disease. Through this procedure, we identified

SUBMITTER: Delivoria DC 

PROVIDER: S-EPMC6795521 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature