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Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use

a technology of inducible factor and compound, which is applied in the direction of biocide, drug composition, peptide/protein ingredients, etc., can solve the problems of low efficiency of enzyme function, and achieve the effect of enhancing hif activity

Inactive Publication Date: 2009-08-27
CORNELL RES FOUNDATION INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to a method for enhancing the activity of HIF (hypoxia-inducible factor) in a cell. This is achieved by contacting the cell with certain compounds such as 3,6-bis[2-(dimethylamino)ethoxy-9h-xanthen-9-onedihydrochloride, 2,8-bis(dimethylaminoacetyl)-dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, oxybendazole, oxyphenazopyridine, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamine, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine. The invention also provides a method for treating neurodegenerative diseases, strokes, and spinal cord injuries by administering the same compounds."

Problems solved by technology

For example, under conditions of reduced oxygen, these enzymes function with low efficiency.

Method used

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  • Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use
  • Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use
  • Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use

Examples

Experimental program
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Effect test

example 1

Tilorone Analogues R-10,874-DA, R-11,567-DA, and R-9536-DA Enhances Hypoxia Inducible Factor-1 in the Nervous System

[0073]HT22 murine hippocampal cells were stably transfected with an enolase 1 promoter-luciferase reporter construct and selected with puromycin. Tilorone analogues R-10,874-DA, R-11,567-DA, and R-9536-DA were tested for their ability to activate a HIF-luciferase reporter. Luciferase activity was measured using a Luciferase Assay System (PROMEGA) according to the manufacture's protocol.

[0074]HIF-1α protein levels were determined in nuclear extracts using a monoclonal anti-HIF-1a antibody (NOVUS Biologicals). Real time RT-PCR was performed in a ABI-7500 instruments using commercial Taqman gene expression assays (Applied BioSystems).

[0075]Male Sprague Dawley rats, weighing 275-350 gm, were used in these experiments. For surgical procedures, anesthesia was induced with 5% isofluorane delivered in oxygen and maintained at 1.5% throughout surgery. Core body temperature was ...

example 2

HIF1α / Carrier Peptide Fusion Protein Enhances HIF Activity

[0078]The peptide designated HIF / ODD / wt contains part of the oxygen dependent domain, including the C-terminal hydroxylation site of human HIF-1α at proline 564 (DDLDEMLAPYIPMDDDFQL; bold P=praline 564). The HIF / ODD / wt peptide and the peptide control with mutation of both prolines to alanine (HIF / ODD / mut; DDLEMLAAYIAMDDDFQL) were rendered cell permeant by fusing each of these peptides to the cell-membrane transduction domain of the human immunodeficiency virus-type 1 tat protein (YGRKKKRRQRR) to obtain two 30 amino acid peptides Tat-HIF / ODD / wt and Tat-HIF / ODD / mut.

[0079]To evaluate the ability of Tat-HIF / ODD peptide to be delivered to cortical neurons efficiently and without toxicity, the chromophore fluorescein isothiocyanate was conjugated to the tat-HIF / ODD / Wt peptide. Tat-HIF / ODD / Wt / FITC peptides (10 μM) were bath applied to rat cortical neuronal cultures from E17 rat embryos. These cultures are approximately 90% neurons a...

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Abstract

The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide.

Description

[0001]The invention described in this application was made with funds from the National Institutes of Health, Grant Numbers NS 39170, NS 40591, and NS 46239. The United States Government has certain rights in this invention.[0002]The invention was also made with funds from New York State, contract number CO19772. New York State has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional activator that regulates the expression of genes involved in adaptation to hypoxic stress. HIF-1 is composed of two subunits referred to as HIF-1α and HIF-1β. These subunits are expressly constitutively. During normal conditions, HIF-1α is targeted to ubiquitination and proteosomal degradation following hydroxylation of HIF-1 at proline 402 and 564 by the enzyme, prolyl hydroxylase.[0004]Prolyl hydroxylases are reported to be oxygen-dependent. For example, under conditions of reduced oxygen, these enzymes function with lo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K31/352A61K31/343A61K31/24A61P25/00
CPCA61K31/58A61K31/24A61K31/343A61K31/352A61P25/00
Inventor RATAN, RAJIV R.SIDDIQ, AMBREENACHAVEZ, JUAN C.
Owner CORNELL RES FOUNDATION INC
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