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Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's A? peptide and reduce its cytotoxicity.

ABSTRACT: The amyloid-? (A?) aggregation pathway is a key target in efforts to discover therapeutics that prevent or delay the onset of Alzheimer's disease. Efforts at rational drug design, however, are hampered by uncertainties about the precise nature of the toxic aggregate. In contrast, high-throughput screening of compound libraries does not require a detailed understanding of the structure of the toxic species, and can provide an unbiased method for the discovery of small molecules that may lead to effective therapeutics. Here, we show that small molecule microarrays (SMMs) represent a particularly promising tool for identifying compounds that bind the A? peptide. Microarray slides with thousands of compounds immobilized on their surface were screened for binding to fluorescently labeled A?. Seventy-nine compounds were identified by the SMM screen, and then assayed for their ability to inhibit the A?-induced killing of PC12 cells. Further experiments focused on exploring the mechanism of rescue for one of these compounds: Electron microscopy and Congo red binding showed that the compound enhances fibril formation, and suggest that it may rescue cells by accelerating A? aggregation past an early toxic oligomer. These findings demonstrate that the SMM screen for binding to A? is effective at identifying compounds that reduce A? toxicity, and can reveal potential therapeutic leads without the biases inherent in methods that focus on inhibitors of aggregation.

SUBMITTER: Chen J

PROVIDER: S-EPMC3063105 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's Aβ peptide and reduce its cytotoxicity.

Chen Jermont J Armstrong Anne H AH Koehler Angela N AN Hecht Michael H MH

Journal of the American Chemical Society 20101109 47

The amyloid-β (Aβ) aggregation pathway is a key target in efforts to discover therapeutics that prevent or delay the onset of Alzheimer's disease. Efforts at rational drug design, however, are hampered by uncertainties about the precise nature of the toxic aggregate. In contrast, high-throughput screening of compound libraries does not require a detailed understanding of the structure of the toxic species, and can provide an unbiased method for the discovery of small molecules that may lead to e ...[more]

PMID: 21062056

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Project description:The transcription factor MYC plays a pivotal role in cancer initiation, progression, and maintenance. However, it has proven difficult to develop small molecule inhibitors of MYC. One attractive route to pharmacological inhibition of MYC has been the prevention of its expression through small molecule-mediated stabilization of the G-quadruplex (G4) present in its promoter. Although molecules that bind globally to quadruplex DNA and influence gene expression are well-known, the identification of new chemical scaffolds that selectively modulate G4-driven genes remains a challenge. Here, we report an approach for the identification of G4-binding small molecules using small molecule microarrays (SMMs). We use the SMM screening platform to identify a novel G4-binding small molecule that inhibits MYC expression in cell models, with minimal impact on the expression of other G4-associated genes. Surface plasmon resonance (SPR) and thermal melt assays demonstrated that this molecule binds reversibly to the MYC G4 with single digit micromolar affinity, and with weaker or no measurable binding to other G4s. Biochemical and cell-based assays demonstrated that the compound effectively silenced MYC transcription and translation via a G4-dependent mechanism of action. The compound induced G1 arrest and was selectively toxic to MYC-driven cancer cell lines containing the G4 in the promoter but had minimal effects in peripheral blood mononucleocytes or a cell line lacking the G4 in its MYC promoter. As a measure of selectivity, gene expression analysis and qPCR experiments demonstrated that MYC and several MYC target genes were downregulated upon treatment with this compound, while the expression of several other G4-driven genes was not affected. In addition to providing a novel chemical scaffold that modulates MYC expression through G4 binding, this work suggests that the SMM screening approach may be broadly useful as an approach for the identification of new G4-binding small molecules.

Dataset Information

Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's A? peptide and reduce its cytotoxicity.

Publications

Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's Aβ peptide and reduce its cytotoxicity.

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