WO2013111714A1 - Agent prophylactique ou thérapeutique pour l'asthme bronchique et méthode de dépistage de ce dernier - Google Patents

Agent prophylactique ou thérapeutique pour l'asthme bronchique et méthode de dépistage de ce dernier Download PDF

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WO2013111714A1
WO2013111714A1 PCT/JP2013/051120 JP2013051120W WO2013111714A1 WO 2013111714 A1 WO2013111714 A1 WO 2013111714A1 JP 2013051120 W JP2013051120 W JP 2013051120W WO 2013111714 A1 WO2013111714 A1 WO 2013111714A1
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heme peroxidase
peroxidase
heme
activity
bronchial asthma
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PCT/JP2013/051120
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English (en)
Japanese (ja)
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出原　賢治
和彦 有馬
鈴木　章一
裕士 白石
昭一郎 太田
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国立大学法人佐賀大学
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Priority to JP2013555252A priority Critical patent/JP6143363B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • C12Q1/28—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase involving peroxidase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns

Definitions

  • the present invention relates to a preventive or therapeutic agent for bronchial asthma and a screening method thereof.
  • Bronchial asthma is a disease characterized by increased airway hypersensitivity to nonspecific stimulating substances, and is a disease that causes clinical symptoms such as cough, sputum, and dyspnea.
  • the therapeutic agents used in the treatment of bronchial asthma are mainly inhaled steroids, which are used in combination with leukotriene receptor antagonists, ⁇ 2 receptor stimulants, theophylline agents and the like.
  • inhaled steroids are highly effective for bronchial asthma, 10-15% of all bronchial asthma patients show steroid resistance, and patients with such steroid resistance are treated with drugs other than inhaled steroids Is required. In addition, in children with bronchial asthma, etc., the use of inhaled steroids may be refrained from the viewpoint of side effects.
  • Non-patent Document 1 thiamazole has been widely used as a therapeutic agent for hyperthyroidism, and its safety has been confirmed.
  • Non-Patent Document 2 agranulocytosis and polyarthritis are known as the main side effects of thiamazole, but the frequency is very low, less than 1%, and skin symptoms such as eczema and itch.
  • Non-Patent Document 3 describes that thiamazole does not cause chromosomal abnormalities in spermatogonia, spermatocytes, and bone marrow cells.
  • An object of the present invention is to provide a prophylactic or therapeutic agent for bronchial asthma that has a different mechanism of action from an inhaled steroid and can replace the inhaled steroid.
  • heme peroxidase in tracheal tissue is a factor that exacerbates bronchial asthma, and heme peroxidase inhibitors are useful for improving the pathology of bronchial asthma As a result, the present invention has been completed.
  • the present invention provides the following preventive or therapeutic agents for bronchial asthma, screening methods for preventive or therapeutic agents for bronchial asthma, and the like.
  • a prophylactic or therapeutic agent for bronchial asthma containing a heme peroxidase inhibitor containing a heme peroxidase inhibitor.
  • the heme peroxidase inhibitor is at least one selected from the group consisting of the following (a) to (h): (a) a compound that inhibits the activity of heme peroxidase, (b) a compound that inhibits the expression of heme peroxidase, (c) an antibody that inhibits the activity of heme peroxidase, (d) siRNA or shRNA against a polynucleotide encoding heme peroxidase, (e) an antisense polynucleotide containing a base sequence complementary to or substantially complementary to the base sequence of a polynucleotide encoding heme peroxidase, or a part thereof, (f) a ribozyme against a polynucleotide encoding heme peroxidase, (g) a variant of heme peroxidase that acts dominant
  • the heme peroxidase inhibitor is at least one selected from the group consisting of the following (a) to (h): (a) a compound that inhibits the activity of heme peroxidase, (b) a compound that inhibits the expression of heme peroxidase, (c) an antibody that inhibits the activity of heme peroxidase, (d) siRNA or shRNA against a polynucleotide encoding heme peroxidase, (e) an antisense polynucleotide containing a base sequence complementary to or substantially complementary to the base sequence of a polynucleotide encoding heme peroxidase, or a part thereof, (f) a ribozyme against a polynucleotide encoding heme peroxidase, (g) a variant of heme peroxidase that acts dominantly negatively on heme peroxida
  • [3a] The method according to [1] above, wherein the heme peroxidase inhibitor is thiamazole.
  • [4a] The method according to any one of [1a] to [3a] above, wherein the bronchial asthma is steroid-resistant bronchial asthma.
  • [5] A method for screening a prophylactic or therapeutic agent for bronchial asthma by contacting a test compound with a cell expressing heme peroxidase and using the activity or expression level of heme peroxidase as an index.
  • a test compound in which the activity or expression level of heme peroxidase in the case of (i) is lower than the activity or expression level of heme peroxidase in the case of (ii) is a candidate compound for a prophylactic or therapeutic agent for bronchial asthma
  • the method according to [6] above, which is selected as [8] A method for screening a prophylactic or therapeutic agent for bronchial asthma by contacting a test compound with heme peroxidase and using the activity of heme peroxidase as an index.
  • a prophylactic or therapeutic agent for bronchial asthma that can improve the pathological condition of bronchial asthma by an action mechanism different from that of a steroid agent is provided.
  • the preventive or therapeutic agent for bronchial asthma according to a preferred embodiment of the present invention is also effective for steroid resistant bronchial asthma patients.
  • Example 1 The experimental result which investigated the effect
  • FIG. 6 shows the results of an experiment examining the effect of OSCN - ions on airway epithelial cells (Example 2). The experimental result which investigated the effect
  • Example 4 The result of another experiment which investigated the effect
  • the present invention provides a prophylactic or therapeutic agent for bronchial asthma containing a heme peroxidase inhibitor.
  • the present invention also provides a method for screening a prophylactic or therapeutic agent for bronchial asthma using the activity or expression level of heme peroxidase as an index.
  • the present inventors considered that some anions which transmits Pendorin forms the asthmatic condition, SCN as such anions - focused on the ion.
  • the present inventors have found that during drinking asthma model mice SCN - since the asthma-like conditions to obtain a result that deterioration in mice was added ions (Fig. 1 (B)), SCN - ions to asthma It was revealed that it was an exacerbation factor.
  • the present inventors consider that SCN ⁇ ions undergo a reaction of SCN ⁇ + H 2 O 2 ⁇ OSCN ⁇ + H 2 O together with hydrogen peroxide (H 2 O 2 ) by heme peroxidase in airway tissues. It was.
  • the inventors of the present invention have obtained the result that the activity of NF- ⁇ B, which is a molecule important for inflammation, is increased by increasing the OSCN ⁇ ion in the cell in the cell culture system experiment (FIG. 2).
  • OSCN - ion was also found to be an exacerbation factor for asthma.
  • the present inventors have revealed that heme peroxidase in the airway tissue is a factor that exacerbates asthma.
  • the present inventor further revealed that inhibiting the activity of heme peroxidase, inhibiting the expression of heme peroxidase, and the like lead to improvement of the pathological condition of bronchial asthma.
  • thiamazole one of the heme peroxidase inhibitors and used as an anti-hyperthyroid drug, was administered to mice, it showed increased airway hypersensitivity and asthma-like conditions such as eosinophilic inflammation. It was able to be suppressed (FIGS. 3 (A) to (C)).
  • Prophylactic or therapeutic agent for bronchial asthma containing heme peroxidase inhibitor provides a prophylactic or therapeutic agent for bronchial asthma containing a heme peroxidase inhibitor.
  • the present invention also provides a method for preventing or treating bronchial asthma, comprising administering a therapeutically effective amount of a heme peroxidase inhibitor to a patient in need of preventing or treating bronchial asthma.
  • Heme peroxidase inhibitor used in the present invention is a family of peroxidases and is a general term for peroxidases containing heme in the active site. In animals, myeloperoxidase (MPO), eosinophil peroxidase (EPO), lactoperoxidase (LPO), thyroid peroxidase (TPO) and the like are included in this family. These heme peroxidases catalyze an oxidation reaction of a substrate substance in a hydrogen peroxide-dependent manner.
  • MPO myeloperoxidase
  • EPO eosinophil peroxidase
  • LPO lactoperoxidase
  • TPO thyroid peroxidase
  • heme peroxidase is not particularly limited, and examples thereof include those derived from humans and those derived from mice.
  • the cDNA sequences and amino acid sequences of various heme peroxidases are as follows.
  • heme peroxidase is used in the sense of including its variants as long as it has substantially the same quality of activity.
  • the mutant include one to a plurality (for example, 1 to 30, 1 to 29, 1 to 28, 1 to 27, 1 to 26, 1 to 26) in the amino acid sequence of the above heme peroxidase. 25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1 15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9 (1 to several), 1-8, 1-7, 1 (-6, 1-5, 1-4, 1-3, 1-2, or 1) amino acids deleted, substituted, inserted, and / or added to the protein. . In general, the smaller the number of amino acids deleted, substituted, inserted or added, the better. Two or more of the amino acid residue deletions, substitutions, insertions and additions may occur simultaneously.
  • the substantially homogeneous activity includes, for example, the activity of heme peroxidase.
  • Substantially homogeneous indicates that their activities are qualitatively (eg, physiologically or pharmacologically) equivalent. Therefore, it is preferable that the activity of heme peroxidase is equivalent (eg, about 0.01 to 100 times, preferably about 0.1 to 10 times, more preferably 0.5 to 2 times). However, the degree of these activities and the molecular weight of the protein Quantitative factors such as may be different.
  • the activity of heme peroxidase means an enzyme activity that catalyzes an oxidation reaction of a substance by peroxide.
  • Heme peroxidase inhibitor means a substance having an activity of inhibiting the activity of heme peroxidase or inhibiting the expression of heme peroxidase.
  • siRNA, shRNA, antibody, antisense, peptide, protein, enzyme and the like can be used in addition to a low molecular weight or high molecular compound.
  • “Inhibiting the activity of heme peroxidase” means inhibiting the enzyme activity of heme peroxidase.
  • ⁇ Inhibiting heme peroxidase expression '' means a series of events from gene encoding the protein to protein production, including inhibition of gene expression of the protein (e.g. transcription (production of mRNA), translation (protein Inhibiting the event of any of the above (including production) means inhibiting the production of the protein.
  • transcription production of mRNA
  • translation protein Inhibiting the event of any of the above (including production) means inhibiting the production of the protein.
  • heme peroxidase inhibitor used in the present invention a substance that inhibits the activity of heme peroxidase, a substance that inhibits the expression of heme peroxidase, or the like is used. Specifically, from the following (a) to (h) And at least one substance selected from the group.
  • “compound” includes low molecular weight compounds and high molecular weight compounds.
  • “Low molecular weight compound” means organic and inorganic substances having a molecular weight of 10,000 or less (preferably a molecular weight of 5,000 or less, more preferably a molecular weight of 2,000 or less, particularly preferably a molecular weight of 700 or less).
  • the “polymer compound” means an organic substance having a molecular weight of over 10,000 (preferably a molecular weight of 50,000 or more, more preferably a molecular weight of 100,000 or more).
  • the activity of heme peroxidase can be measured by a known method or a method analogous thereto.
  • the activity of heme peroxidase is, for example, a method using a color reaction generated by oxidation of 3,3 ′, 5,5′-tetramethylbenzidine (TMB) (Thomas, EL et al, J Dent Res 73,544-555, 1994), etc. Can be measured.
  • TMB 5,5′-tetramethylbenzidine
  • the expression level of heme peroxidase can also be measured by a known method or a method analogous thereto.
  • the expression level of heme peroxidase is, for example, measuring the protein level of heme peroxidase (Free (Radic Biol Med, 49,1354-60,2010), measuring the amount of hemeperoxidase mRNA (J Immunol, 167, 1672- 1682, 2001), etc.
  • the compound (including salt form) that inhibits heme peroxidase activity is not particularly limited as long as it is a compound that can inhibit heme peroxidase activity. Examples thereof include a compound that binds to peroxidase and inhibits its enzyme activity, or a salt thereof.
  • Such a compound may be, for example, a compound selected from peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, cell extracts, plant extracts, animal tissue extracts, plasma and the like.
  • the compound may be a novel compound or a known compound.
  • the salt form compounds include physiologically acceptable metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. It is done.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid And salts with benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
  • physiologically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid
  • organic acids such as tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • examples of the compound capable of inhibiting the activity of heme peroxidase include thiamazole, propylthiouracil, dapsone, azide and the like. Alternatively, such a compound can also be obtained by a screening method described later. These compounds that inhibit the activity of heme peroxidase can be used alone or in combination of two or more thereof as necessary.
  • the compound that inhibits heme peroxidase expression is not particularly limited as long as it can inhibit heme peroxidase expression.
  • a gene encoding heme peroxidase (DNA) encodes heme peroxidase.
  • examples thereof include compounds that inhibit transcription to mRNA, and (ii) compounds that inhibit translation from heme peroxidase-encoding mRNA into heme peroxidase.
  • any compound that inhibits transcription of heme peroxidase-encoding gene (DNA) into heme peroxidase-encoding mRNA any compound that inhibits transcription of heme peroxidase-encoding gene (DNA) into mRNA
  • a compound that binds to a factor involved in transcription from a gene (DNA) encoding heme peroxidase to mRNA and inhibits transcription can be mentioned.
  • any compound that inhibits translation from heme peroxidase-encoding mRNA into heme peroxidase is not particularly limited. Examples thereof include compounds that bind to a factor involved in translation from heme peroxidase-encoding mRNA into heme peroxidase and inhibit the translation.
  • Such a compound can be obtained, for example, by a screening method described later.
  • the compounds that inhibit the expression of heme peroxidase can be used alone or in combination of two or more thereof as necessary.
  • Antibody that inhibits the activity of heme peroxidase since the purpose is to inhibit the activity of heme peroxidase, any antibody that inhibits the activity of heme peroxidase can be used.
  • Such an antibody includes an antibody that can recognize heme peroxidase or a partial peptide thereof, and that inhibits the activity of heme peroxidase.
  • Such an antibody may be either a polyclonal antibody or a monoclonal antibody.
  • the antibody to heme peroxidase or a partial peptide thereof used in the present invention can be produced according to a known method for producing an antibody or antiserum using heme peroxidase or a partial peptide thereof as an antigen.
  • siRNA or shRNA against a polynucleotide encoding heme peroxidase Double-stranded RNA that has RNAi action on a polynucleotide encoding heme peroxidase (e.g., siRNA or shRNA against a polynucleotide encoding heme peroxidase) has low toxicity, and translates the gene encoding heme peroxidase. Since it can suppress and the expression of heme peroxidase can be suppressed, it can be used suitably as a substance which inhibits the expression of heme peroxidase.
  • Such double-stranded RNA having an RNAi action on a polynucleotide encoding heme peroxidase includes a double-stranded RNA containing a part of RNA encoding heme peroxidase (e.g., a polynucleotide encoding heme peroxidase).
  • SiRNA for nucleotides small (short) interfering RNA
  • shRNA small (short) hairpin RNA
  • Such double-stranded RNA is obtained by a known method (e.g., Nature, 411, 494, 2001; Special Tables 2002-516062; U.S. Patent Application Publication No. 2002/086356; Nature Genetics, 24). Volume, 180-183, 2000; Genesis, 26, 240-244, 2000; Nature, 407, 319-320, 2002; Genes & Dev., 16, 948-958, 2002 Proc. Natl. Acad. Sci. USA., 99, 5515-5520, 2002; Science, 296, 550-553, 2002; Proc. Natl. Acad. Sci.
  • the length of the double-stranded RNA having RNAi action used in the present invention is usually 17 to 30 bases, preferably 19 to 27 bases, more preferably 20 to 22 bases.
  • an antisense polynucleotide containing a base sequence complementary to or substantially complementary to the base sequence of a polynucleotide encoding heme peroxidase, or a part thereof, preferably a polynucleotide (preferably DNA) encoding heme peroxidase (hereinafter referred to as DNA)
  • DNA a polynucleotide encoding heme peroxidase
  • the base sequence substantially complementary to the DNA used in the present invention is, for example, the entire base sequence of the base sequence complementary to the DNA used in the present invention (that is, the complementary strand of the DNA used in the present invention) or Examples thereof include base sequences having homology of about 70% or more, preferably about 80% or more, more preferably about 90% or more, and most preferably about 95% or more with a partial base sequence.
  • the base sequence of the portion encoding the N-terminal site of heme peroxidase for example, the start An antisense polynucleotide having a homology of about 70% or more, preferably about 80% or more, more preferably about 90% or more, and most preferably about 95% or more with a complementary strand (such as a base sequence near a codon)
  • an antisense polynucleotide directed to RNA degradation by RNaseH it is about 70% or more, preferably about 80% or more, more preferably about 80% or more with the complementary strand of the entire base sequence of DNA used in the present invention including introns.
  • Each of the antisense polynucleotides having 90% or more, most preferably about 95% or more homology is preferred.
  • the antisense polynucleotide is usually composed of about 10 to 40 bases, preferably about 15 to 30 bases.
  • the phosphate residue (phosphate) of each nucleotide constituting the antisense DNA is changed to a chemically modified phosphate residue such as phosphorothioate, methylphosphonate, phosphorodithionate, etc. May be substituted.
  • the sugar (deoxyribose) of each nucleotide may be substituted with a chemically modified sugar structure such as 2′-O-methylation, and the base part (pyrimidine, purine) is also chemically modified. It may be any one as long as it hybridizes with DNA having the base sequence of the polynucleotide encoding heme peroxidase.
  • These antisense polynucleotides can be produced using a known DNA synthesizer or the like.
  • the antisense polynucleotide of the present invention may be altered or contain modified sugars, bases and bonds, and may be provided in special forms such as liposomes, microspheres, or applied by gene therapy. Can be provided in an added form.
  • the additional form can be used as a polycationic substance such as polylysine that acts to neutralize the charge of the phosphate group skeleton, a lipid that enhances the interaction with the cell membrane or increases the uptake of nucleic acid ( Examples include hydrophobic ones such as phospholipid and cholesterol.
  • Preferred lipids for addition include cholesterol and its derivatives (eg, cholesteryl chloroformate, cholic acid, etc.).
  • nucleic acid can be attached via a base, sugar, intramolecular nucleoside bond.
  • the other group include a cap group specifically arranged at the 3 'end or 5' end of a nucleic acid for preventing degradation by nucleases such as exonuclease and RNase.
  • capping groups include, but are not limited to, hydroxyl protecting groups known in the art, including glycols such as polyethylene glycol and tetraethylene glycol.
  • Ribozyme against a polynucleotide encoding heme peroxidase A polynucleotide having ribozyme activity against a polynucleotide encoding heme peroxidase can suppress the expression of heme peroxidase, and therefore inhibits the expression of heme peroxidase. Can be suitably used.
  • Such ribozymes are prepared by known methods (eg, TRENDS in Molecular Medicine, 7, 221, 2001; FEBS Lett., 228, 228, 1988; FEBS Lett., 239, 285, 1988). Nucl. Acids. Res., 17, 7059, 1989; Nature, 323, 349, 1986; Nucl. Acids.
  • RNA encoding heme peroxidase examples include a portion (RNA fragment) close to the cleavage site on the RNA encoding heme peroxidase that can be cleaved by a known ribozyme.
  • the ribozymes include large ribozymes such as group I introns and M1 RNA contained in RNaseP, and small ribozymes such as hammerhead and hairpin types (Protein Nucleic Acid Enzyme, 35, 2191, 1990).
  • hammerhead ribozymes include FEBS Lett., 228, 228, 1988; FEBS Lett., 239, 285, 1988; Protein Nucleic Acid Enzyme, 35, 2191, 1990; Nucl.
  • heme peroxidase that acts dominantly against heme peroxidase or a polynucleotide that encodes it
  • the term “mutant of a protein that acts dominantly against heme peroxidase” means a protein that has an action of inhibiting (eliminating or reducing) the activity of heme peroxidase when it is expressed. (See Taira Yoshikazu, edited by gene function inhibition experiment, Yodosha, pp. 26-32, 2001).
  • an aptamer for heme peroxidase can inhibit the activity and function of heme peroxidase, it can be suitably used as a substance that inhibits the activity of heme peroxidase.
  • Aptamers are obtained using a known method, for example, the SELEX (systematic evolution of ligands by exponential enrichment) method (Annual Review of Medicine 56, 555-583, 2005).
  • the structure of an aptamer can be determined using a known method, and an aptamer is produced according to a known method based on the structure.
  • a medicament containing the above-mentioned heme peroxidase inhibitor is used as a prophylactic or therapeutic agent for bronchial asthma. Since the heme peroxidase inhibitor of the preferred embodiment has a preventive / therapeutic effect on bronchial asthma, it may be administered for therapeutic purposes to patients with bronchial asthma, or for the purpose of prevention for patients who must consider prevention or recurrence of bronchial asthma Can also be administered. In a preferred embodiment of the invention, the heme peroxidase inhibitor is administered for therapeutic purposes.
  • Bronchial asthma is a disease characterized by increased airway hypersensitivity to nonspecific stimulating substances, and is a disease that causes clinical symptoms such as cough, sputum, and dyspnea.
  • the preventive or therapeutic agent of the present invention can prevent or treat at least one of these symptoms.
  • the preventive or therapeutic agent of the present invention can improve the pathological condition of bronchial asthma by an action mechanism different from that of an inhaled steroid. For this reason, the preventive or therapeutic agent of the preferable aspect of this invention is useful for the treatment of the patient resistant to a steroid.
  • the above-mentioned heme peroxidase inhibitor can be formulated according to conventional means and used as a prophylactic or therapeutic agent for bronchial asthma.
  • the heme peroxidase inhibitor is thiamazole.
  • compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules). Syrup, emulsion, suspension and the like.
  • Such a composition is produced by a method known per se, and contains a carrier, diluent or excipient usually used in the pharmaceutical field.
  • a carrier for example, lactose, starch, sucrose, magnesium stearate and the like are used as carriers and excipients for tablets.
  • compositions for parenteral administration for example, injections, suppositories, eye drops, nasal drops, spray inhalants, coating agents, patches and the like are used, and the injections are intravenous injections and subcutaneous injections.
  • dosage forms such as intradermal injection, intramuscular injection, infusion injection, intraarticular injection and the like.
  • Such an injection is prepared by a method known per se, for example, by dissolving, suspending or emulsifying the active ingredient in a sterile aqueous or oily liquid usually used for injections.
  • aqueous solution for injection for example, isotonic solution containing physiological saline, glucose and other adjuvants, etc.
  • solubilizers such as alcohol (eg, ethanol), polyalcohol (eg, Propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct-of-hydrogenated-castor-oil)) and the like may be used in combination.
  • oily liquid for example, sesame oil, soybean oil and the like are used, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent.
  • the prepared injection solution is usually filled in a suitable ampoule.
  • Suppositories used for rectal administration are prepared by mixing the above active ingredients with a conventional suppository base. Eye drops, nasal drops, spray inhalants, suppositories, coating agents, patches and the like are also prepared according to methods known per se using the above active ingredients.
  • compositions may contain other active ingredients (for example, other prophylactic or therapeutic agents for bronchial asthma) as long as undesirable interactions are not caused by blending with the active ingredients. Further, it may be used in combination with other active ingredients (for example, other prophylactic or therapeutic agents for bronchial asthma).
  • active ingredients for example, other prophylactic or therapeutic agents for bronchial asthma
  • the dose of the active ingredient of the preventive or therapeutic agent of the present invention varies depending on its action, target disease, administration subject, symptom, administration route, etc., but for example, when administered orally, generally in adults (weight 60 kg)
  • the dosage of the active ingredient varies depending on the target disease, administration subject, symptom, administration route, etc., but when administered in the form of an injection, it is generally an adult (with a body weight of 60 kg).
  • the antisense polynucleotide can be formulated and administered according to a method known per se.
  • an appropriate vector such as a retrovirus vector, an adenovirus vector, an adenovirus associated virus vector, etc.
  • a human or mammal eg, rat, Rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.
  • the antisense polynucleotide can be formulated as it is or with a physiologically recognized carrier such as an adjuvant for promoting intake, and can be administered by a gene gun or a catheter such as a hydrogel catheter.
  • the above-mentioned antisense polynucleotide is formulated alone (injection) together with a carrier such as liposome and administered to veins, etc. Also good.
  • the double-stranded RNA, ribozyme, mutant of heme peroxidase that acts dominantly against the heme peroxidase or the polynucleotide encoding the same can be formulated and administered in the same manner as the antisense polynucleotide. it can.
  • the above antibodies, aptamers and the like can be administered per se or as an appropriate pharmaceutical composition.
  • the pharmaceutical composition used for the administration comprises the antibody or a salt thereof and a pharmacologically acceptable carrier, diluent or excipient.
  • Such compositions are provided as dosage forms suitable for oral or parenteral administration (eg, intravenous injection). Preferably it is provided as an inhalant.
  • the present invention relates to a method for screening a prophylactic or therapeutic agent for bronchial asthma by contacting a test compound with a cell expressing heme peroxidase and using the heme peroxidase activity or heme peroxidase expression level as an index. Provide a way to do it.
  • the present invention also provides a method for screening a prophylactic or therapeutic agent for bronchial asthma by contacting a test compound with heme peroxidase and using the activity of heme peroxidase as an index.
  • a preferred embodiment of the screening method of the present invention is a method comprising evaluating a heme peroxidase inhibitory activity of a test compound and selecting a compound having a peroxidase inhibitory activity.
  • the selected compound having peroxidase inhibitory activity is a candidate compound for a prophylactic or therapeutic agent for bronchial asthma.
  • Heme peroxidase inhibitory activity means an activity that reduces or suppresses the activity of heme peroxidase or the expression level of heme peroxidase.
  • test compound examples include peptides, proteins, antibodies, non-peptidic compounds, synthetic compounds, fermentation products, cell extracts, plant extracts, animal tissue extracts, plasma, etc. These compounds are novel compounds. It may be a known compound.
  • the test compound may form a salt, and as the salt of the test compound, physiologically acceptable metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, bases And salts with acidic or acidic amino acids.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid And salts with benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
  • a test compound in some methods for screening a prophylactic or therapeutic agent for bronchial asthma according to the present invention, (i) when a test compound is contacted with a cell expressing heme peroxidase, and (ii) the test compound expresses heme peroxidase Comparison of the activity or expression level of heme peroxidase in the cells when not in contact with the cells is performed.
  • a test compound is contacted with cells expressing heme peroxidase.
  • the origin of the “cell” used is not particularly limited, but is, for example, a cell derived from a human, a mouse or the like, and preferably a cell derived from a human.
  • Cells expressing heme peroxidase used in the screening method of the present invention are, for example, airway epithelial cells, neutrophils, eosinophils and the like.
  • the “cell expressing heme peroxidase” used in the screening method of the present invention can also be prepared by a general genetic engineering technique.
  • the activity or expression level of heme peroxidase is measured. Specifically, for example, in the cases (i) and (ii) above, the cells are cultured, and the activity or expression level of heme peroxidase in each case is measured.
  • the measurement of the activity or expression level of heme peroxidase can be performed, for example, by the above-described method for measuring the activity or expression level of heme peroxidase.
  • a compound that inhibits the activity or expression of heme peroxidase is selected as compared with the case where the test compound is not contacted (control).
  • a test compound that decreases by 50% or more can be selected as a compound that inhibits the activity of heme peroxidase.
  • test compound in which the expression level of heme peroxidase in the case of (i) is lower than the expression level of heme peroxidase in the case of (ii), in particular, 10% or more, 20% or more, 30% or more Test compounds that decrease by 40% or more, or 50% or more can be selected as compounds that inhibit heme peroxidase expression.
  • the activity of heme peroxidase is compared without using cells. That is, the activity of heme peroxidase is compared when (i) the test compound is contacted with heme peroxidase and (ii) when the test compound is not contacted with heme peroxidase.
  • the test compound is contacted with heme peroxidase.
  • a test compound is added to a reaction system that causes a reaction of SCN ⁇ + H 2 O 2 ⁇ OSCN ⁇ + H 2 O using heme peroxidase.
  • Heme peroxidase is as described above, but it is preferable to use one purified as heme peroxidase.
  • the reaction is preferably performed in a test tube.
  • the activity of heme peroxidase is measured. Specifically, for example, in the cases (i) and (ii) above, the activity of heme peroxidase in each case is measured.
  • the activity of heme peroxidase can be measured, for example, by the above-described method for measuring the activity of heme peroxidase.
  • a compound that inhibits the activity of heme peroxidase is selected as compared with the case where the test compound is not contacted (control).
  • a test compound that decreases by 50% or more can be selected as a compound that inhibits the activity of heme peroxidase.
  • the selected candidate compound is administered to an experimental animal (eg, mouse, rat, etc.), and the effect of the selected candidate compound on the prevention or treatment of bronchial asthma is confirmed.
  • an experimental animal eg, mouse, rat, etc.
  • the effect of the selected candidate compound on the prevention or treatment of bronchial asthma is confirmed.
  • FIG. 1 (A) shows the experimental protocol. As shown in the protocol of FIG. 1 (A), drinking water containing 20 mM thiocyanate ion (SCN ⁇ ) was taken daily from Day 0. Sensitize with allergen ovalbumin on days 0 and 12 (sensitization 1, 2), and ovalbumin exposure on days 22, 23, 24 (exposure 1-3), airway 24 hours after exposure 3 Hypersensitivity was measured. The group in which the experiment was conducted with this protocol is defined as an asthma group (+ SCN) or a sensitized group (+ SCN).
  • SCN ⁇ 20 mM thiocyanate ion
  • a non-asthma group (-SCN), a non-asthma group (+ SCN) group, and an asthma group (-SCN) were used.
  • the non-asthma group (-SCN) is indicated as the non-sensitized (-SCN) group in FIG. 1 (B), and sensitization with ovalbumin was not performed, and thiocyanate was used instead of drinking thiocyanate ion.
  • the experiment was performed using the same protocol as the sensitized group (+ SCN) except that drinking water containing no ions was administered.
  • the non-asthma group (+ SCN) group is shown as the non-sensitized (+ SCN) group in FIG.
  • non-asthmatic group (+ SCN) group is the same as the sensitized (+ SCN) group except that no sensitization with ovalbumin Experiments were performed using the same protocol.
  • the asthma group (-SCN) is labeled as a sensitized (-SCN) group in FIG. 1 (B), except that the thiocyanate ion-free drinking water was administered instead of the thiocyanate ion drinking water, Experiments were performed using the same protocol as the sensitized (+ SCN) group.
  • Airway hypersensitivity was measured according to the method described in Matsushita, H. et al. Int Immunol 22, 739-747, 2010. Specifically, airway hypersensitivity to mesacholine was measured using unrestrained whole body plethysmography (BUXCO) 24 hours after the final exposure. Mesacholine (purchased from sigma) was diluted with physiological saline and used at the concentration shown in FIG. 1 (B).
  • BUXCO unrestrained whole body plethysmography
  • FIG. 1 (B) The results are shown in FIG. 1 (B). Increased airway hyperresponsiveness was observed in the sensitized group compared to the non-sensitized group. Then, in the sensitization Yes group, SCN - in drinking water Yes group (with sensitization (+ SCN) group), SCN - further enhancement of airway hyperresponsiveness compared to drinking water without the group (with sensitization (-SCN) group) was recognized. From the above results, it was revealed that SCN - ion is an exacerbation factor for asthma.
  • Example 2 Effect of OSCN - ion on airway epithelial cells
  • the following reaction was caused in a cell culture medium.
  • Airway epithelial cells (NCI-H292 cells) were suspended in RPMI1640 / 5% FCS / 50 mM HEPES medium, and 1.8 ⁇ 10 6 cells were seeded in a 6-well plate. After overnight culture, NaSCN (final concentration 1 mM), GOX (final concentration 9 mUnits / ml), and LPO (final concentration 40 U / ml) were added to the cell culture medium. After further incubation for 5 hours, a nuclear extract was prepared using the method of Schreiber et al (Nucleic Acids Res.
  • FIG. 3 (A) shows the experimental protocol. As shown in the protocol of FIG. 3 (A), sensitization was performed with ovalbumin, an allergen, on day 0 and 12 (sensitization 1, 2), and ovalbumin exposure was performed on days 22, 26, 30 ( Exposure 1-3). From Day 20, I took drinking water containing 0.2 mg / ml thiamazole every day.
  • asthma group (with thiamazole).
  • the asthma group (with thiamazole) is represented as a thiamazole administration group in FIGS. 3 (B) and 3 (C).
  • a non-asthma group and an asthma group were used.
  • the non-asthma group is described as a control group in FIGS. 3 (B) and 3 (C), and sensitization with ovalbumin was not performed, and drinking water containing no thiamazole was administered instead of drinking thiamazole. Except for this, this group was tested using the same protocol as the asthma group (with thiamazole).
  • the asthma group (without thiamazole) is labeled as the asthma group in FIGS. 3 (B) and (C), and the asthma group (thiamazole) was administered except that thiazazole-free drinking was administered instead of thiamazole drinking. This is a group in which an experiment was conducted with the same protocol as (Yes).
  • BALB / c mice (6 weeks old, male) obtained from Japan SLC were used.
  • Drinking water containing thiamazole was prepared by dissolving 20 mg thiamazole (Wako Pure Chemical Industries) in 100 ml sterile distilled water (final concentration 0.2 mg / ml).
  • Airway hypersensitivity was measured according to the method described in Matsushita, H. et al. Int Immunol 22, 739-747, 2010. Specifically, airway hypersensitivity to mesacholine was measured using unrestrained whole body plethysmography (BUXCO) 24 hours after the final exposure. Mesacholine was diluted with physiological saline and used at the concentration shown in FIG. 3 (B).
  • BUXCO unrestrained whole body plethysmography
  • Bronchoalveolar lavage fluid was collected and analyzed according to the method described in Matsushita, H. et al. Int Immunol 22, 739-747, 2010. Specifically, bronchoalveolar lavage fluid was prepared using 1.5 ml of physiological saline, and the total number of cells in this lavage fluid was measured with a hemocytometer (CDA500; Sysmex), and then the cells in the lavage fluid were cytospun and Diff-Quik The number of eosinophils was measured by staining with (Sysmex).
  • FIG. 3 (B) The measurement results of airway hypersensitivity are shown in FIG. 3 (B).
  • suppression of airway hypersensitivity was observed compared to the group not receiving thiamazole (asthma group).
  • FIG. 3 (C) The analysis result of bronchoalveolar lavage fluid is shown in FIG. 3 (C).
  • suppression of the number of eosinophils in the bronchoalveolar lavage fluid was observed compared to the group not receiving thiamazole (asthma group).
  • Example 4 Comparison of effects of thiamazole and steroids in bronchial asthma model mice
  • inhibition of heme peroxidase activity, inhibition of heme peroxidase expression, and the like are related to the steroid drug dexamethasone (DEX) Even when compared with the administration of, it has been confirmed that it exhibits an excellent preventive or therapeutic effect on bronchial asthma.
  • FIG. 4 (A) shows the experimental protocol. As shown in the protocol of FIG. 4 (A), sensitization was performed with ovalbumin, an allergen, on Day 0 and 12 (sensitization 1, 2), and exposure to ovalbumin was performed on Day 22, 23, 24 ( Exposure 1-3).
  • a non-asthma group to which no drug was administered and an asthma group to which no drug was administered were used.
  • the non-asthmatic group that did not receive the drug did not receive sensitization with ovalbumin, and the same protocol as the asthmatic group (thiamazole), except that it received drinking water that did not contain thiamazole instead of drinking thiamazole.
  • the asthma group to which no drug is administered is a group in which an experiment was conducted according to the same protocol as the asthma group (thiamazole), except that drinking water containing no thiamazole was administered instead of drinking thiamazole.
  • BALB / c mice (6 weeks old, female) obtained from Japan SLC were used for the experiment.
  • Drinking water containing thiamazole was prepared by dissolving 20 mg thiamazole (Wako Pure Chemical Industries) in 100 ml sterile distilled water (final concentration 0.2 mg / ml).
  • the physiological saline containing DEX was prepared and administered as follows. Water-soluble DEX (cat No. D2915, Sigma-Aldrich Japan) was dissolved in physiological saline to a concentration of 25 ⁇ g / ml or 75 ⁇ g / ml, and 200 ⁇ l of each was intraperitoneally administered.
  • the method of preparation, sensitization, and exposure of ovalbumin was performed according to the method described in Example 3.
  • Airway hypersensitivity was measured according to the method described in Matsushita, H. et al. Int Immunol 22, 739-747, 2010. Specifically, airway hypersensitivity to mesacholine was measured using unrestrained whole body plethysmography (BUXCO) 24 hours after the final exposure. Mesacholine was diluted with physiological saline and used at the concentration shown in FIG. 4 (B).
  • BUXCO unrestrained whole body plethysmography
  • Bronchoalveolar lavage fluid was collected and analyzed according to the method described in Matsushita, H. et al. Int Immunol 22, 739-747, 2010. Specifically, bronchoalveolar lavage fluid was prepared using 1.5 ml of physiological saline, and the total number of cells in the lavage fluid was measured with a hemocytometer (CDA500; Sysmex). Furthermore, the cells in the washing solution were treated with respective antibodies against Ly-6G antigen (neutrophil marker), siglec-F antigen (eosinophil marker), CD3 antigen (T cell marker), and F4 / 80 antigen (macrophage marker).
  • Ly-6G antigen neutral marker
  • siglec-F antigen eosinophil marker
  • CD3 antigen T cell marker
  • F4 / 80 antigen microphage marker
  • FIG. 4 (B) The measurement results of airway hypersensitivity are shown in FIG. 4 (B).
  • the asthma group (thiamazole) further suppression of airway hypersensitivity was observed compared to the asthma group (DEX 5 ⁇ g) and the asthma group (DEX 15 ⁇ g).
  • the analysis results of bronchoalveolar lavage fluid are shown in FIGS. 4 (C) and 4 (D).
  • the number of cells in the bronchoalveolar lavage fluid eosinophil count, neutrophil count, macrophage count, And suppression of T cell count. From the above, inhibiting heme peroxidase activity, inhibiting heme peroxidase expression, etc. may be more effective in preventing or treating bronchial asthma than when administering a steroid. It could be confirmed.
  • [SEQ ID NO: 1] This is the cDNA sequence of human lactoperoxidase.
  • [SEQ ID NO: 2] This is the amino acid sequence of human lactoperoxidase.
  • [SEQ ID NO: 3] This is the cDNA sequence of mouse lactoperoxidase.
  • [SEQ ID NO: 4] This is the amino acid sequence of mouse lactoperoxidase.
  • [SEQ ID NO: 5] This is the cDNA sequence of human myeloperoxidase.
  • [SEQ ID NO: 6] is an amino acid sequence of human myeloperoxidase.
  • [SEQ ID NO: 7] This is the cDNA sequence of mouse myeloperoxidase.
  • [SEQ ID NO: 8] This is the amino acid sequence of mouse myeloperoxidase.
  • [SEQ ID NO: 9] This is the cDNA sequence of human eosinophil peroxidase.
  • [SEQ ID NO: 10] This is the amino acid sequence of human eosinophil peroxidase.
  • [SEQ ID NO: 11] This is the cDNA sequence of mouse eosinophil peroxidase.
  • [SEQ ID NO: 12] This is the amino acid sequence of mouse eosinophil peroxidase.
  • [SEQ ID NO: 13] This is the cDNA sequence of human thyroid peroxidase.
  • [SEQ ID NO: 14] This is the amino acid sequence of human thyroid peroxidase.
  • [SEQ ID NO: 15] This is the cDNA sequence of mouse thyroid peroxidase.
  • [SEQ ID NO: 16] Amino acid sequence of mouse thyroid peroxidase.

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Abstract

La présente invention concerne un agent prophylactique ou thérapeutique pour l'asthme bronchique, ledit agent comprenant un inhibiteur de la peroxydase de l'hème. Par conséquent, l'invention concerne un agent prophylactique ou thérapeutique pour l'asthme bronchique, qui présente un mécanisme fonctionnel différent du mécanisme fonctionnel des stéroïdes inhalés et est utilisable comme substitut des stéroïdes inhalés.
PCT/JP2013/051120 2012-01-24 2013-01-22 Agent prophylactique ou thérapeutique pour l'asthme bronchique et méthode de dépistage de ce dernier WO2013111714A1 (fr)

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WO2010099523A1 (fr) * 2009-02-27 2010-09-02 University Of Cincinnati Procédé de traitement de maladie réactive des voies respiratoires

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010099523A1 (fr) * 2009-02-27 2010-09-02 University Of Cincinnati Procédé de traitement de maladie réactive des voies respiratoires

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