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Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof

A compound and composition technology, applied in the field of heat shock transcription factor activation compounds, can solve problems affecting functions, incomplete folding of proteins, etc.

Inactive Publication Date: 2011-06-08
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, small errors in the genetic blueprint lead to incomplete folding of the protein, which affects its function

Method used

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  • Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
  • Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
  • Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0122] This example describes the optimization of growth conditions for the DTY512 strain. Such as image 3 It was demonstrated that the growth conditions of the yhsfΔ strain (DTY512 strain) of the pRS424-GPD-hHSF1 plasmid implicating 1) the yeast HSF gene coupled to the GAL promoter, and 2) hHSF1 expression were from petri dish to 96-well microplate format to optimize. Cells were grown in synthetic complete medium lacking uracil and tryptophan in the presence of the non-inducing / non-repressing carbon source raffinose (2%) to select for plasmid maintenance. A concentration of galactose (0.01%) was empirically identified that induced sufficient levels of yeast HSF to enhance yeast cell viability while sensitizing cells after addition of 4% glucose to enhance glucose repression of yeast HSF expression. Selected cells were grown to mid log phase in selective synthetic complete medium containing 2% raffinose and 0.01% galactose. The culture was then diluted to ~5,000 cells / ml i...

Embodiment II

[0124] This example describes the identification of candidate HSF1 activating compounds. Such as image 3 As shown, suitable growth conditions were identified, applying yeast-based human HSF1 activators screened into high-throughput 96-well grid plates for galactose induction and glucose repression parameters. This screen evaluated a combinatorial chemical library of ~10,500 different compounds constructed from ~75 individual scaffolds in the PPD library (PPD Discovery Research, Research Triangle Park, NC). Although this was an appropriately sized screen, ~50 different library components were identified that would adequately enhance yeast cell growth within 48-96 hours of inoculation at a concentration of 10 micromolar. Figure 4A Small samples of 5 compounds that stimulate yeast cell growth with varying potency, a DMSO solvent control and one compound that was negative in this screen are shown. Subsequent analysis of 32 more potent compounds confirmed that the potency of al...

Embodiment III

[0128] This example describes the materials and methods used in Examples IV-VII.

[0129] cell culture. Wild-type and hsf1 - / - mouse embryonic fibroblast (MEF) cells were grown in DMEM + 10% FBS (37 o C, 5% CO 2 )middle. For MEF cells, at the time of experiment, mix 6X10 5 cells were seeded in each well of a 6-well plate. Cells were incubated under these conditions for an additional 12 hours, at which point the cells were washed twice with IX PBS before the growth medium was switched to serum-free OptiMEM medium (Invitrogen). For PC-12 cells, make 5X10 5 Cells were seeded in each well of a 6-well plate in 2 ml of serum-free OptiMEM medium and incubated under these conditions for an additional 12 hours. After 12 hours, HSF1A or DMSO was added to MEF or PC-12 cells, and at 37 o C for 15 hours.

[0130] western blotting. After 15 hr of treatment, cells were washed twice in IX PBS and collected by scraping. Cells were lysed using lysis buffer solution (25mM Tris, 150m...

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PUM

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Abstract

The present invention relates to HSF activating compounds, methods for their discovery, and their research and therapeutic uses. In particular, the present invention provides compounds capable of facilitating HSFl activation, and methods of using such compounds as therapeutic agents to treat a number of conditions associated with protein misfolding.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to pending US Provisional Patent Application Serial No. 61 / 053,513, filed May 15, 2008, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under GM059911-08 and GM076954 awarded by the National Institutes of Health. The government has certain rights in this invention. field of invention [0005] The present invention relates to heat shock transcription factor (HSF) activating compounds, methods for their discovery, and their research and therapeutic applications. In particular, the invention provides compounds capable of promoting HSF1 activation, and methods of using such compounds as therapeutic agents to treat a number of disease-related conditions and other pathophysiological conditions caused by or associated with defective protein foldin...

Claims

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Application Information

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IPC IPC(8): A61K31/415A61K31/4155A61K31/426A61P25/28A61P25/16A61P35/00
CPCA61K31/415C07D231/40A61K31/426C07D277/42A61K45/06C07D277/60C07K14/47C07D409/04A61K31/4155A61P25/16A61P25/28A61P35/00A61K2300/00
Inventor D.J.蒂勒D.W.尼夫
Owner DUKE UNIV
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