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Compositions and methods for counteracting effects of reactive oxygen species and free radicals

a technology of reactive oxygen species and free radicals, applied in the field of antioxidative compounds, can solve the problems of reducing the level of ros or free radicals in the cell, affecting the antioxidative activity of the cell, so as to reduce, eliminate or prevent an undesirable elevation of ros and free radicals, and restore the age-related reduction of constitutive antioxidative enzymes.

Inactive Publication Date: 2005-04-28
ISCHEMIX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030] The invention also provides methods of counteracting the effects of ROS and free radicals in cells and tissues comprising contacting the cells or tissues with a peptide compound described herein. In a preferred embodiment of the invention, the peptide compounds of the invention stimulate (upregulate) expression of a gene(s) encoding superoxide dismutase (SOD) and / or catalase (CAT) enzymes, which enzymes are capable of detoxifying ROS and free radicals in cells and tissues of animals, including humans and other mammals. Preferably, gene expression for both SOD and CAT proteins are upregulated by contacting cells or tissues with a peptide compound of this invention. Treating cells or tissues with a peptide compound described herein may elevate the expression of gene(s) encoding SOD and / or CAT to sufficiently high levels to provide significantly increased detoxification of ROS and free radicals compared to untreated cells or tissues.
[0031] Patients having a variety of diseases or conditions have been found to possess undesirable levels of ROS and / or free radicals. In a preferred embodiment of the invention, a composition comprising a peptide compound described herein may be used therapeutically to counteract the effects of ROS and free radicals present in the body and / or prophylactically to decrease or prevent an undesirable elevation in the levels of ROS and free radicals associated with particular diseases, conditions, drug treatments, or disorders. Specifically, this invention provides methods in which a composition comprising a peptide compound described herein is administered to an individual to treat or prevent a disease or condition that is characterized by the generation of toxic levels of ROS or free radicals, including but not limited to tissue and / or cognitive degeneration during aging (senescence), senility, Tardive dyskinesia, cerebral ischemia (stroke), myocardial infarct (heart attack), head trauma, brain and / or spinal cord trauma, reperfusion damage, oxygen toxicity in premature infants, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, diabetes, ulcerative colitis, human leukemia and other cancers characterized by elevation of ROS or free radicals, age-related elevation of ROS or free radicals, Down syndrome, macular degeneration, cataracts, schizophrenia, epilepsy, septic shock, polytraumatous shock, burn injuries and radiation-induced elevation of ROS and free radicals (including UV-induced skin damage).
[0032] In a particularly preferred embodiment, this invention provides methods in which a composition comprising a peptide compound described herein is administered to an individual to lessen or eliminate side effects caused by drug regimens that generate ROS and free radicals. A number of drugs have been found to cause undesirable elevation of levels of ROS or free radicals as a toxic side effect. Such drugs include doxorubicin, daunorubicn, BCNU (carmustine) and related compounds such as methyl-BCNU and CCNU, and neuroleptics, such as clozapine. As an adjuvant to such therapies, the peptide compounds of this invention can be used to decrease the severity of or eliminate these damaging side effects. Accordingly, the peptides of this invention may be administered to treat or prevent drug-induced elevation of ROS or free radicals, such as occurs during treatment with neuroleptic drugs as in Tardive dyskinesia.
[0035] The invention also provides therapeutic compositions comprising a peptide compound of the invention in a pharmaceutically acceptable buffer for administration to an individual to eliminate, reduce, or prevent the generation of toxic levels of ROS or free radicals in cells or tissues.

Problems solved by technology

Even a relatively small elevation in ROS or free radical levels in a cell can be damaging.
Likewise, a release or increase of ROS or free radicals in extracellular fluid can jeopardize the surrounding tissue and result in tissue destruction and necrosis.
In addition, an elevation of ROS and free radicals has also been linked with reperfusion damage after renal transplants.
Despite many years of focused research effort, the use of SOD and other lazaroids has not provided a successful prophylactic or therapeutic tool for addressing the diseases, disorders and other conditions caused by or characterized by the generation of ROS and free radicals.

Method used

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  • Compositions and methods for counteracting effects of reactive oxygen species and free radicals
  • Compositions and methods for counteracting effects of reactive oxygen species and free radicals
  • Compositions and methods for counteracting effects of reactive oxygen species and free radicals

Examples

Experimental program
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Effect test

example 1

Synthesis of Representative Peptide Compounds

[0138] The following representative peptide compounds were synthesized by solid phase Merrifield synthesis (Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)):

CMX-9236D([DHA]-Lys Lys Asp Gly Asp Gly Asp(SEQ ID NO: 26)Phe Ala Ile Asp Ala Pro Glu),CMX-9236(Lys Lys Asp Gly Asp Gly Asp Phe(SEQ ID NO: 26)Ala Ile Asp Ala Pro Glu),CMX-11540([Lip]-Asp Gly Asp Gly Asp Phe Ala(SEQ ID NO: 16)Ile Asp Ala Pro Glu),CMX-99661([Gga] Asp Gly Asp Gly Phe Ala),(SEQ ID NO: 5)CMX-99655([Ac] Asp Gly Asp Gly Phe Ala),(SEQ ID NO: 5)CMX-9960([Palm] Asp Gly Asp Gly Phe Ala),(SEQ ID NO: 5)CMX-9963([Ac]-Asp Gly Asp Gly Asp Phe(SEQ ID NO: 6)Ala),CMX-9967([Ac]-Asp Gly Asp),CMX-9901(Lys Lys Gln Tyr Lys Leu Gly Ser(SEQ ID NO: 27)Lys Thr Gly Pro Gly Gln),CMX-8933(Lys Lys Glu Thr Leu Gln Phe Arg),(SEQ ID NO: 24)CMX-9902(Lys Lys Asp Gly Asp Gly Asp Phe(SEQ ID NO: 28)Ala),CMX-99658([Ac]-Gln Thr Leu Gln Phe Arg),(SEQ ID NO: 2)Lys Lys Gln Thr Leu Gln Phe Arg,(SEQ ID NO: 2...

example 2

Upregulation of Superoxide Dismutase (SOD) and Catalase (CAT) in Mammalian Cells By Peptide Compounds CMX-9236, CMX-9963, and CMX-9967

Upregulation of SOD

[0142] The RT-PCR method (see, for example, Innis et al., PCR Protocols: A Guide to Methods and Applications, (Academic Press, San Diego, 1990)) was used to investigate the upregulation of the specific mRNA that codes for the enzyme superoxide dismutase (SOD).

[0143] Primary cortical cultures were obtained by growing newborn rat brain cortical cells in Delbecco's modified Eagle medium supplemented with 25 μg / ml of gentamycin and 10% fetal calf serum. The cells were isolated from the E-21 cortex of rat brain, plated at a density of 1×105 per ml and grown to confluence within four to five days in an atmosphere containing air and 5% CO2 at 37° C. as described in Cornell-Bell et al., Science, 247: 470-473 (1990) and Cell Calcium, 12: 185-204 (1991). Cultures were grown in 20 ml flasks as a monolayer and then exposed to various concen...

example 3

Upregulation of AP-1 Transcription Factor in Mammalian Cells By Peptide Compounds

[0158] Immediately prior to use, a 1.0 mg aliquot of a peptide compound was dissolved in 1.0 ml of 5% xylitol in HBSS (Hanks' Balanced Salt Solution, Hanks and Wallace, Proc. Soc. Exp. Biol. Med. 71:196 (1949)), the pH neutralized with 0.1 N NaOH, and the solution filter sterilized. Each peptide compound migrated as a single peak on HPLC column (C-18). The structure of each peptide compound was confirmed by amino acid analysis, and its molecular weight was verified by mass spectroscopy.

[0159] Nuclear extracts for electrophoretic mobility shift assays (EMSAs) were prepared as described previously (Adams et al., J. Leukocyte Biol., 62: 865-873 (1997)) using 1.0-2.0×107 cells per sample. All buffers were freshly supplemented with dithiothreitol (DTT, 0.5 mM), protease inhibitors: PMSF (0.5 mM), chymostatin, peptstatin-A, aprotinin, antipain, leupeptin (each at 1 μg / ml), and phosphatase inhibitors: NaF (1...

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Abstract

Peptide compounds and methods for upregulating expression of a gene encoding an antioxidative enzyme, such as superoxide dismutase or catalase, to counteract harmful oxidative effects of reactive oxygen species and other free radicals are described. The peptide compounds may be used to treat or prevent diseases and conditions characterized by undesirable elevation of reactive oxygen species and other free radicals, to upregulate AP-1 gene expression, and to treat pain. The peptide compounds may be used as components of pharmaceuticals and dietary supplements.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application No. 60 / 166,381, filed Nov. 18, 1999, which is incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention is in the field of antioxidative compounds, in particular, pharmaceutical and nutraceutical compounds for use in therapeutic and prophylactic treatments of diseases and conditions characterized by undesirable levels of reactive oxygen species and free radicals. BACKGROUND TO THE INVENTION [0003] Biological organisms generate harmful reactive oxygen species (ROS) and various free radicals in the course of normal metabolic activities of tissues such as brain, heart, lung, and muscle tissue (Halliwell, B. and Gutteridge, J. M. C., eds. Free Radicals in Biology and Medicine, (Oxford: Clarendon Press, 1989)). The most reactive and, therefore, toxic ROS and free radicals include the superoxide anion (O2.−), singlet oxygen, hydrogen peroxide (H2O2)...

Claims

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Application Information

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IPC IPC(8): A61K38/00C07K5/113C07K7/06C07K7/08
CPCA61K38/00C07K7/08C07K7/06C07K5/1021A61P9/10A61P39/06
Inventor SHASHOUA, VICTOR E.
Owner ISCHEMIX
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