ArticleProtein science : a publication of the Protein Society2009
Discovery of amyloid-beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 47 citations in OpenAlex.
- A genetically encoded selection for amyloid-β oligomer binders.Nature chemical biology · 2025Article
- Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection.Nature chemical biology · 2025Article
- 1,3,5-Triazine: A Promising Molecular Scaffold for Novel Agents for the Treatment of Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Mangosteen Pericarp and Its Bioactive Xanthones: Potential Therapeutic Value in Alzheimer's Disease, Parkinson's Disease, and Depression with Pharmacokinetic and Safety Profiles.International journal of molecular sciences · 2020Review
- Effect of C-terminus amidation of AβRSC advances · 2020Article
- Therapeutic Potential of Direct Clearance of the Amyloid-β in Alzheimer's Disease.Brain sciences · 2020Article
- Molecular interactions with redox sites and salt bridges modulate the anti-aggregatory effect of flavonoid, tannin and cardenolide moieties against amyloid-beta (1-42) in silico.In silico pharmacology · 2017Article
- An in vivo platform for identifying inhibitors of protein aggregation.Nature chemical biology · 2016Article
- In vitro neuroprotective activities of compounds from Angelica shikokiana Makino.Molecules (Basel, Switzerland) · 2015Article
- Screening strategies to identify HSP70 modulators to treat Alzheimer's disease.Drug design, development and therapy · 2015Review
- Optimizing recombinant antibodies for intracellular function using hitchhiker-mediated survival selection.Protein engineering, design & selection : PEDS · 2014Article
- Effects of secondary metabolite extract from Phomopsis occulta on β-amyloid aggregation.PloS one · 2014Article
- Tanshinones inhibit amyloid aggregation by amyloid-β peptide, disaggregate amyloid fibrils, and protect cultured cells.ACS chemical neuroscience · 2013Article
- A bacterial export system for generating extracellular amyloid aggregates.Nature protocols · 2013Article
- Generating extracellular amyloid aggregates using E. coli cells.Genes & development · 2012Article
- Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors.Microbial cell factories · 2012Article
- On the design of broad based screening assays to identify potential pharmacological chaperones of protein misfolding diseases.Current topics in medicinal chemistry · 2012Review
- Development and validation of a yeast high-throughput screen for inhibitors of Aβ₄₂ oligomerization.Disease models & mechanisms · 2011Article
- Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: dual activity as cholinesterase and Aβ-aggregation inhibitors.Bioorganic & medicinal chemistry · 2011Article
- Genetic selection designed to stabilize proteins uncovers a chaperone called Spy.Nature structural & molecular biology · 2011Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Genetic and biochemical studies suggest that Alzheimer's disease (AD) is caused by a series of events initiated by the production and subsequent aggregation of the Alzheimer's amyloid beta peptide (Abeta), the so-called amyloid cascade hypothesis. Thus, a logical approach to treating AD is the development of small molecule inhibitors that either block the proteases that generate Abeta from its precursor (beta- and gamma-secretases) or interrupt and/or reverse Abeta aggregation. To identify potent inhibitors of Abeta aggregation, we have developed a high-throughput screen based on an earlier selection that effectively paired the folding quality control feature of the Escherichia coli Tat protein export system with aggregation of the 42-residue AD pathogenesis effecter Abeta42. Specifically, a tripartite fusion between the Tat-dependent export signal ssTorA, the Abeta42 peptide and the beta-lactamase (Bla) reporter enzyme was found to be export incompetent due to aggregation of the Abeta42 moiety. Here, we reasoned that small, cell-permeable molecules that inhibited Abeta42 aggregation would render the ssTorA-Abeta42-Bla chimera competent for Tat export to the periplasm where Bla is active against beta-lactam antibiotics such as ampicillin. Using a fluorescence-based version of our assay, we screened a library of triazine derivatives and isolated four nontoxic, cell-permeable compounds that promoted efficient Tat-dependent export of ssTorA-Abeta42-Bla. Each of these was subsequently shown to be a bona fide inhibitor of Abeta42 aggregation using a standard thioflavin T fibrillization assay, thereby highlighting the utility of our bacterial assay as a useful screen for antiaggregation factors under physiological conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.