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Compounds for enhancing hypoxia inducible factor activity and methods of use


Title: Compounds for enhancing hypoxia inducible factor activity and methods of use.
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. ...

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USPTO Applicaton #: #20090215687 - Class: $ApplicationNatlClass (USPTO) -
Inventors: Rajiv R. Ratan, Ambreena Siddiq, Juan C. Chavez



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The Patent Description & Claims data below is from USPTO Patent Application 20090215687, Compounds for enhancing hypoxia inducible factor activity and methods of use.

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.

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

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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.

Prolyl hydroxylases are reported to be oxygen-dependent. For example, under conditions of reduced oxygen, these enzymes function with low efficiency. As a result, HIF-1α is not hydroxylated, and thus not targeted to ubiquitination and degradation. Accordingly, HIF-1α becomes stabilized, and can bind HIF-1β to activate genes involved in adaptation to oxidative stress.

Oxidative stress is reported to be associated with numerous diseases and conditions, including stroke, hypoxia, ischemia, spinal cord injury and neurodegenerative conditions. Thus, compounds which enhance the activity of HIF-1α protein are beneficial for treating conditions and diseases associated with oxidative stress.

SUMMARY

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OF THE INVENTION

In one embodiment, the present invention relates to a method for enhancing HIF activity in a cell in need thereof. The method comprises 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.

In another embodiment, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method comprises administering to the mammal 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, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In yet another embodiment, the invention provides a method for treating hypoxia in a mammal in need thereof. The method comprises administering to the mammal 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, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In a further embodiment, the invention provides a method for treating stroke in a mammal in need thereof. The method comprises administering to the mammal 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, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine.

In yet a further embodiment, the invention provides a method for treating spinal cord injury in a mammal in need thereof. The method comprises administering to the mammal 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, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine.

In another embodiment, the invention provides a method for treating ischemia in a mammal in need thereof. The method comprises administering to the mammal 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, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Chemical structures of compounds.

FIG. 2. Amino acid sequence of HIFα protein, NCBI GenBank Accession No. Q16665.

FIG. 3. Tilorone analogues increase HIF-1 transcriptional activity.

FIG. 4. Tilorone analogues induce the expression of HIF-1 target genes in the rat cerebral cortex.

FIG. 5. A cell permeant, peptide inhibitor of the HIF prolyl 4-hydroxylase, but not a mutant control, induces expression of HIF-dependent genes. Tat-HIF/wt peptide (100 μM) but not a corresponding peptide with the C-terminal proline hydroxylation site of HIF-1α mutated (Tat-HIF/mut, 100 μM) significantly enhances the activity of a hypoxia response element driven reporter in cortical neurons (* corresponds to p<0.05 compared to control by paired T-test). The low molecular weight P4H inhibitor, FG-0041(40 μM) was used as a positive control.

FIG. 6. A cell permeant, peptide inhibitor of the HIF 4-hydroxylase, but not a mutant control, prevents oxidative glutamate toxicity. The glutamate analog, homocysteate (HCA) (5 mM) was added to cortical neurons (1 DIV) with or without Tat-HIF/wt peptide (30, 40, 50, 100 and 200 μM), Tat-HIF/mut peptide (200 μM), DFO (100 μM) and 3,4 DHB (10 μM). Twenty-four hours later cell viability was determined using the MTT assay. Graph depicts mean +/− SE for three experiments performed in triplicate (* denotes p<0.05 from HCA treated cultures by ANOVA and Student-Newman Keuls tests for control, Tat-HIF/wt, Tat-HIF/mut, DFO and 3,4 DHB).

DETAILED DESCRIPTION

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OF THE INVENTION Method for Enhancing HIF Activity

In another aspect, the invention provides a method for enhancing HIF activity in a cell in need thereof. The method comprises contacting the cell with an effective amount of any one, or any combination, 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 HIFalpha protein fused to a carrier peptide.

The HIF activity can be enhanced in any cell in need thereof. A cell in need of enhancing HIF activity includes cells that are, for example, suffering from trauma, injury, hypoxia, etc. Such cells include those discussed above.

The cell can be contacted with the compound by any method known to those in the art. For example, the cell can be contacted with the compound by incubating the cell and compound in vitro.

Alternatively, the cell can be contacted with the compound in vivo. The compound and cell can be contacted in vivo by any suitable method known to in the art, including the administration methods described below.

Method for Treating Neurodegenerative Disease or Condition

In one aspect, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method for treating a neurodegenerative disease or condition comprises administering to the mammal an effective amount of any one, or any combination, 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, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Neurodegenerative disease or condition typically refers to a disorder generally characterized by gradual and progressive loss of cells, tissue and/or organ of the central or peripheral nervous system. Examples of such cells, tissues and organs include, the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.

Any mammal suffering from any neurodegenerative disease or condition can be treated in accordance with the method of the present invention. For example, the neurodegenerative disease or condition can be an acute condition. Acute conditions generally occur as a result of trauma to a cell, tissue and/or organ of the nervous system. The trauma can, for example, partially or completely block blood flow to the cell, tissue and/or organ. Examples of acute neurodegenerative conditions include head injury and brain injury.

Alternatively, the neurodegenerative disease or condition can be a chronic neurodegenerative condition. Examples of chronic neurodegenerative diseases and conditions include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (also known as Lou Gherig's disease).

Method for Treating Hypoxia

In another aspect, the invention provides a method for treating hypoxia in a mammal in need thereof. The method for treating hypoxia comprises administering to the mammal an effective amount of any one, or any combination, 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, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Any mammal suffering from hypoxia can be treated in accordance with the method of the present invention. Hypoxia generally refers to a lack of oxygen to cells, organs, and/or tissues. Hypoxia can be caused by, for example, ischemia, anemia and chemical modification of blood, such as carboxyhemoglobin, etc.

Hypoxia can occur in any cell, organ, and/or tissue. Examples of cells, organs, and/or tissues which can be subjected to hypoxia include neuronal cells (e.g., neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia), brain, spinal cord, kidney cells, intestinal cells, heart and cardiac muscle cells such as myocytes, skin cells, etc.

Method for Treating Stroke

In yet another aspect, the invention provides a method for treating stroke in a mammal in need thereof. The method for treating stroke comprises administering to the mammal an effective amount of any one, or any combination, 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, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine.

Any mammal suffering from stroke can be treated in accordance with the method of the present invention. Stroke is a type of cardiovascular disease that generally involves the interruption of blood flow to and/or within the brain. The interruption of blood flow can be due to, for example, a blockage or rupture of an artery or vessel. The blockage typically occurs from a blood clot. As a result of the interruption of blood flow, the brain does not receive sufficient amounts of blood.

Method for Treating Spinal Cord Injury

In a further aspect, the invention provides a method for treating spinal cord injury in a mammal in need thereof. The method for treating spinal cord injury comprises administering to the mammal an effective amount of any one, or any combination, 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, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine.

Any mammal suffering from spinal cord injury can be treated in accordance with the method of the present invention. The spinal cord is the major bundle of nerves that carry nerve impulses to and from the brain to the rest of the body. The spinal cord is surrounded by rings of bone referred to as vertebra.

Spinal cord injury refers to any damage to the spinal cord. The damage typically results in loss of function, such as mobility or feeling. Damage to the spinal cord can occur, for example, as a result or trauma (car accident, gunshot, falls, etc.) or disease (polio, spina bifida, Friedreich's Ataxia, etc).

Any injury to the spinal cord can be treated in accordance with the method of the present invention. For example, the injury can be a complete injury to the spinal cord. Complete injury typically refers to the lack of function (e.g., no sensation and no voluntary movement) below the site of injury. Both sides of the body are usually affected.

Alternatively, the injury may be an incomplete injury to the spinal cord. An incomplete injury generally refers to some function below the site of injury. For instance, a person with an incomplete injury may be able to move one limb more than another, may be able to feel parts of the body that cannot be moved, or may have more functioning on one side of the body than the other, etc.

Method for Treating Ischemia

In yet a further aspect, the invention provides a method for treating ischemia in a mammal in need thereof. The method comprises administering to the mammal an effective amount of any one, or any combination, 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, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Any mammal suffering from ischemia can be treated in accordance with the method of the present invention. Ischemia generally refers to a condition of decreased blood flow to an organ, tissue and/or cell. The decrease in blood flow can be caused by, for example, constriction (e.g., hypoxemic vasoconstriction) or obstruction (e.g., clot, atherosclerotic plaque) of a blood vessel.

Ischemia can occur in any cell, organ, and/or tissue. Examples of cells, organs, and/or tissues which can be subjected to ischemia include neuronal cells (e.g., neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia), brain, spinal cord, intestinal cells, kidney cells, heart and cardiac muscle cells such as myocytes, etc.

Compounds

Compounds useful in the methods of the present invention are 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, and hydralazine, the chemical structures of which are shown in FIG. 1.

The brand name, generic name, chemical name, alternative spelling, etc. of some of the compounds are listed in FIG. 1. For example, the compound “phenazopyridine hydrochloride” may also be referred to as “phenazopyrinine hydrochloride.”

The compounds can be in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a well-tolerated, nontoxic salt prepared from any one of the compounds mentioned above, and an acid or base. The acids may be inorganic or organic acids of any one of the compounds mentioned above. Examples of inorganic acids include hydrochloric, hydrobromic, nitric hydroiodic, sulfuric, and phosphoric acids. Examples of organic acids include carboxylic and sulfonic acids. The radical of the organic acids may be aliphatic or aromatic. Some examples of organic acids include formic, acetic, phenylacetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, stearic, sulfanilic, alginic, tartaric, citric, gluconic, gulonic, arylsulfonic, and galacturonic acids. Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

Throughout this specification, parameters are defined by maximum and minimum amounts. Each minimum amount can be combined with each maximum amount to define a range.

In one aspect of the invention, the compound is HIF alpha (HIFα) protein fused to a carrier peptide. The HIFα protein portion of the fusion protein can include all of the amino acid sequence of HIFα. The amino acid sequence of HIFα is shown in FIG. 2.

Alternatively, the HIFα protein portion of the fusion protein is a fragment of the amino acid sequence of HIFα containing either one or both prolines at amino acid position numbers 402 and 564 of full length HIFα. Thus, the fragment can be any fragment containing the proline at position 402 and/or position 564 of full length HIFα.

The fragment of HIFα comprises a minimum of four amino acid, preferably about six amino acids, more preferably about eight, even more preferably about twelve, yet even more preferably about fifteen, and most preferably a minimum of about nineteen amino acids. The maximum number of amino acids in the fragment is 825, preferably about 750, more preferably about 600, even more preferably about 500, yet even more preferably about 400, further more preferably about 200, and most preferably a maximum of about 100.

For example, the fragment can comprise the fifteen to nineteen, 31 to 79, or 121 to 200, etc. amino acid sequence corresponding to the residues adjacent to, and/or surrounding, proline residue 402 and/or 564, of HIFα.

In a preferred embodiment, the fragment comprises proline residues 402 and 562 and all residues between the proline residues.

The HIFα portion of the fusion protein can comprise functional analogs of, the entire HIFα amino acid sequence, or fragments described above. The functional analogs must satisfy function and contain either one or both prolines at amino acid position numbers 402 and 564 of full length HIFα. The functional analog may, for example, be a substitution variant of full length HIFα, or a substitution variant of a fragment described above.

Suitable substitution variants of full length HIFα or fragment include conservative amino acid substitutions. Amino acids may be grouped according to their physicochemical characteristics as follows:

(a) Non-polar amino acids: Ala(A) Ser(S) Thr(T) Pro(P) Gly(G);

(b) Acidic amino acids: Asn(N) Asp(D) Glu(E) Gln(Q);

(c) Basic amino acids: His(H) Arg(R) Lys(K);

(d) Hydrophobic amino acids: Met(M) Leu(L) Ile(I) Val(V); and

(e) Aromatic amino acids: Phe(F) Tyr(Y) Trp(W) His(H).

Substitutions of an amino acid in a peptide by another amino acid in the same group is referred to as a conservative substitution. Conservative substitutions tend to preserve the physicochemical characteristics of the original peptide. In contrast, substitutions of an amino acid in a peptide by another amino acid in a different group is generally more likely to alter the characteristics of the original peptide.

A carrier peptide, in general, refers to any synthetic or naturally occurring amino acid sequence that can transduce or assist in the transduction of a protein or peptide into a cell. Carrier peptides are also referred to a protein transduction domains.

The carrier peptide portion of the fusion protein can be any protein transduction domain or carrier peptide known to those skilled in the art. Examples of protein transduction domains include HIV tat, herpes simplex virus VP22 transcription factor, and Drosophila homeotic transcription factor encoded by antennapedia gene. Such transduction domains are disclosed in Schwarze et al., 2000, Trends in Pharmacol. Sci., 21:45-48.

Other examples of suitable carrier peptides include the protein transduction domains disclosed in U.S. Pat. Nos. 6,221,355 to Dowdy; 5,652,122 to Frankel et al. The protein transduction domains of U.S. Pat. Nos. 6,221,355 and 5,652,122 are hereby incorporated by reference.

Further examples of carrier peptides include aromatic-cationic peptides comprising (i) at least one net positive charge, (ii) a minimum of three amino acids, (iii) a maximum of about twenty amino acids, (iv) a relationship between the minimum number of net positive charges (pm) and the total number of amino acid residues (r) wherein 3pm is the largest number that is less than or equal to r+1, and (v) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (pt) wherein 3a is the largest number that is less than or equal to pt+1, except that when a is 1, pt may also be 1.

The definition and description of aromatic-cationic peptides, and tables listing examples of aromatic-cationic peptides are disclosed in U.S. application Ser. No. 10/838,135 filed on May 3, 2004 of Szeto, et al. and assigned to Cornell Research Foundation, Inc.: The definition, description, tables and examples of aromatic-cationic peptides disclosed in U.S. application Ser. No. 10/838,135 are hereby incorporated by reference.

For example, the carrier peptide can be any one of the aromatic-cationic peptides shown below in Tables 1 and 2.

TABLE 1


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stats Patent Info
Application #
US 20090215687 A1
Publish Date
08/27/2009
Document #
File Date
12/31/1969
USPTO Class
Other USPTO Classes
International Class
/
Drawings
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