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WO2013118606A1 - Médicament destiné à prévenir ou à traiter la malaria et procédé de criblage permettant de l'identifier - Google Patents

Médicament destiné à prévenir ou à traiter la malaria et procédé de criblage permettant de l'identifier Download PDF

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Publication number
WO2013118606A1
WO2013118606A1 PCT/JP2013/051829 JP2013051829W WO2013118606A1 WO 2013118606 A1 WO2013118606 A1 WO 2013118606A1 JP 2013051829 W JP2013051829 W JP 2013051829W WO 2013118606 A1 WO2013118606 A1 WO 2013118606A1
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WIPO (PCT)
Prior art keywords
tocopherol
malaria
compound
αttp
preventive
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English (en)
Japanese (ja)
Inventor
元督 七里
鈴木　宏志
コスタス マリア シェルリー ヘルバス
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National Institute of Advanced Industrial Science and Technology AIST
Obihiro University of Agriculture and Veterinary Medicine NUC
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National Institute of Advanced Industrial Science and Technology AIST
Obihiro University of Agriculture and Veterinary Medicine NUC
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Priority to JP2013557467A priority Critical patent/JP6083534B2/ja
Publication of WO2013118606A1 publication Critical patent/WO2013118606A1/fr
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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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a preventive or therapeutic agent for malaria.
  • Non-Patent Document 1 describes that the mechanism of action of antimalarial drugs such as quinine, chloroquine, and clotrimazole is complex formation with heme.
  • Non-patent document 2 suggests that past epidemiological observations suggest that a deficiency of micronutrients, particularly vitamin E, may induce resistance to protozoal infection.
  • Non-Patent Documents 3 and 4 the amount of ⁇ -tocopherol in mice lacking ⁇ -tocopherol transfer protein ( ⁇ TTP), a protein that regulates the level of vitamin E ( ⁇ -tocopherol) in the blood, decreases, and the protozoan murine malaria It has been described to acquire resistance to infectious diseases.
  • ⁇ TTP ⁇ -tocopherol transfer protein
  • vitamin E Since vitamin E is contained in a relatively large amount in many foods, it is difficult to induce vitamin E deficiency, and it is considered impractical to use vitamin E deficiency for the prevention or treatment of protozoan infection. It was.
  • Non-Patent Document 5 probucol, which is a therapeutic drug for hyperlipidemia, has an activity of inhibiting the ATP-binding cassette transporter A1 (ABCA1) protein that releases ⁇ -tocopherol from the liver into the plasma. It is described that plasma ⁇ -tocopherol concentration can be reduced by oral administration of probucol. However, even when probucol is administered to reduce the ⁇ -tocopherol concentration in plasma, the amount of ⁇ -tocopherol in erythrocytes hardly changes.
  • ABCA1 ATP-binding cassette transporter A1
  • Non-Patent Document 6 discloses that patients receiving probucol showed an average 14% decrease in plasma vitamin E concentration, but this 14% decrease was less than individual differences, and probucol was a vitamin. It has not been known that the plasma concentration of E can be significantly reduced.
  • Non-Patent Document 7 describes that chloroquine suppresses ⁇ TTP-mediated ⁇ -tocopherol secretion, but the mechanism of action of chloroquine was thought to involve complex formation with iron as described above. Reference 7 was not recognized as disclosing a new antimalarial mechanism of action of chloroquine.
  • An object of the present invention is to provide a preventive or therapeutic agent for malaria that has no side effects, can prevent the onset of malaria, and has a therapeutic effect even when administered after suffering from malaria, and a screening method thereof.
  • the present inventors have investigated the effect of treatment with malaria on probucol, which can reduce the concentration of ⁇ -tocopherol in plasma but hardly changes the amount of vitamin E ( ⁇ -tocopherol) in erythrocytes. was found to be able to dramatically reduce the mortality due to malaria despite the fact that it has not changed, and further studies have been completed.
  • a prophylactic or therapeutic agent for malaria containing an effective amount of a compound that lowers the blood concentration of ⁇ -tocopherol.
  • the compound is selected from the group consisting of an ABCA1 transporter inhibitor, an ⁇ TTP inhibitor, an ⁇ -tocopherol absorption inhibitor, and an ⁇ -tocopherol metabolism promoter.
  • the compound is probucol.
  • cells are cultured in the presence of a test compound in a medium containing ⁇ -tocopherol ester taken up into cells, and ⁇ -tocopherol ester-hydrolyzed intracellularly is released to the outside of the cells.
  • a method for screening a preventive or therapeutic agent for malaria characterized by comprising a step of evaluating the release of.
  • ⁇ -tocopherol ester is labeled ⁇ -tocopherol ester.
  • a method for screening a preventive or therapeutic agent for malaria comprising the step of evaluating the movement of ⁇ -TTP into the cell membrane in the presence of a test compound.
  • a method for treating or preventing malaria comprising administering an effective amount of a compound that decreases the blood concentration of ⁇ -tocopherol to a patient in need of treatment or prevention of malaria. Provided.
  • a compound that decreases the blood concentration of ⁇ -tocopherol for the manufacture of a preventive or therapeutic agent for malaria.
  • a compound that decreases the blood concentration of ⁇ -tocopherol for use as a preventive or therapeutic agent for malaria is provided.
  • the preventive or therapeutic agent for malaria according to the present invention is highly effective against chloroquine resistant strains.
  • A is a feeding schedule of experimental animals
  • B is a graph of protozoan infection rate against days after infection
  • C is a graph of survival rate against days after infection.
  • probucol significantly reduces the mortality rate of malaria infection.
  • A is a feeding schedule of experimental animals
  • B is a graph of protozoan infection rate against days after infection
  • C is a graph of survival rate against days after infection.
  • probucol significantly reduces the mortality rate of malaria infection.
  • Vitamin E is a fat-soluble antioxidant and is a generic name for four types of tocopherols ( ⁇ -, ⁇ -, ⁇ -, ⁇ -) and four types of tocotrienols ( ⁇ -, ⁇ -, ⁇ -, ⁇ -).
  • ⁇ -tocopherol has the highest activity and is present in the highest concentration in blood of mammals including humans. Therefore, in the present invention, ⁇ -tocopherol has been focused on, but it is considered that the preventive or therapeutic agent for malaria of the present invention lowers the blood concentration of vitamin E and lowers the blood concentration of the total amount of tocopherol.
  • the compounds serving as the active ingredients of the present invention widely include compounds capable of reducing the blood concentration of ⁇ -tocopherol (concentration in blood, plasma or serum).
  • the compound is preferably used in patients infected with malaria or subjects with a possibility of malaria infection in an amount (effective amount) necessary to reduce the blood concentration of ⁇ -tocopherol (vitamin E), preferably ⁇ -tocopherol. Malaria can be prevented or treated by administering an amount necessary to significantly reduce the blood concentration of (vitamin E).
  • the average value of blood concentration in humans is decreased, and it is desirable to decrease significantly.
  • the degree of decrease in the blood concentration of ⁇ -tocopherol is, for example, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more on average, based on the blood concentration before administration of the active ingredient, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more. Therefore, the “effective amount” in the present specification refers to the average blood concentration of ⁇ -tocopherol, for example, 15% or more, 20% or more, 25% or more, based on the blood concentration before administration of the active ingredient.
  • the lower limit of the daily dose is 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 5000 mg
  • the upper limit is 10,000 mg, 9000 mg, 8000 mg, 7000 mg, 6000 mg is mentioned. Any combination of these upper and lower limits (eg, 1200 mg to 10000 mg) is exemplified as an effective amount of probucol.
  • the effective amount of the active ingredient other than probucol can be appropriately determined with reference to the effective amount of probucol.
  • the blood concentration of ⁇ -tocopherol gradually decreases by the administration of the preventive or therapeutic agent for malaria according to the present invention.
  • the preferred plasma concentration of ⁇ -tocopherol (human, adult) after lowering the blood concentration is 3.8 ⁇ M or less, 3.6 ⁇ M or less, 3.4 ⁇ M or less, 3.2 ⁇ M or less, 3.0 ⁇ M or less, 2.8 ⁇ M or less 2.6 ⁇ M or less, 2.4 ⁇ M or less, 2.2 ⁇ M or less, 2.0 ⁇ M or less, 1.8 ⁇ M or less, 1.6 ⁇ M or less, 1.4 ⁇ M or less, 1.2 ⁇ M or less, 1.0 ⁇ M or less, 0.8 ⁇ M or less 0.6 ⁇ M or less, 0.4 ⁇ M or less, or 0.2 ⁇ M or less.
  • the active ingredient of the present invention only needs to reduce the blood concentration of ⁇ -tocopherol, and even if a large amount of ⁇ -tocopherol is present in the body, the concentration in the blood only needs to be reduced.
  • a compound that regulates biodistribution may be used as an active ingredient, and ⁇ -tocopherol may be decomposed or excreted to reduce the total amount of ⁇ -tocopherol in the living body.
  • a compound that regulates the biodistribution of ⁇ -tocopherol is preferable because it can restore the blood concentration of ⁇ -tocopherol promptly after malaria treatment and has lower side effects.
  • ⁇ significantly decreased '' in the blood concentration of ⁇ -tocopherol means that the blood concentration of ⁇ -tocopherol decreases with a statistically significant difference, specifically P ⁇ 0.05, or Includes the case of P ⁇ 0.01.
  • the malaria-preventing drug of the present invention is less likely to suffer from malaria infection by taking 3 days or more before malaria infection, preferably 1 week or more, more preferably 2 weeks or more before malaria infection. Symptoms of malaria are mild and less likely to become severe. For example, when traveling to an area where there is a possibility of malaria infection, a traveler can significantly reduce the risk of malaria infection by taking the malaria prevention or treatment drug of the present invention before and during travel. .
  • the malaria preventive or therapeutic agent of the present invention has low side effects, so that it can be taken for a long period of time including prevention, unlike conventional antimalarial agents with strong side effects.
  • the antimalarial drug of the present invention can suppress the growth of malaria, promote the healing of malaria, and reduce the mortality even when taken after malaria infection.
  • vitamin E examples include, for example, a compound that suppresses release of ⁇ -tocopherol from cells into the blood, metabolism of ⁇ -tocopherol in blood, and / or Alternatively, a compound that promotes degradation, a compound that suppresses the absorption of ⁇ -tocopherol, and the like can be mentioned, and a compound having such an action can be used as an active ingredient of a preventive or therapeutic agent for malaria.
  • a compound that suppresses the release of ⁇ -tocopherol from cells into the blood is preferred as an active ingredient because it has rapid action.
  • Compounds that suppress the release of ⁇ -tocopherol into cells from the blood include, for example, ABCA1 transporter inhibitor, ⁇ TTP expression inhibitor, ⁇ TTP and ⁇ -tocopherol binding inhibitor, ⁇ TTP and ABCA1 binding inhibitor, etc. It broadly encompasses compounds that inhibit the pathway by which tocopherols migrate from intracellular to blood.
  • Preferred active ingredients of the present invention are probucol and other ABCA1 transporter inhibitors, ⁇ TTP inhibitors, ⁇ -tocopherol absorption inhibitors, and ⁇ -tocopherol metabolism promoters.
  • ABCA1 transporter inhibitors The following i) to iv) are mentioned: i) glyburide ii) 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) Am J Clin Nutr. 2009; 89 (1): 177-84. iii) Cyclosporin A (Arterioscler Thromb Vasc Biol. 2004; 24: 2155-61.) iv) ABCA1 expression inhibitor
  • ⁇ -tocopherol transfer protein ( ⁇ TTP) inhibitors A wide range of agents that inhibit ⁇ TTP expression, such as siRNA, shRNA, antisense RNA, miRNA, or ribozyme, or release these RNA molecules in cells An expression vector etc. are mentioned.
  • a drug that inhibits the function of ⁇ TTP by binding to ⁇ TTP competitively with ⁇ -tocopherol a drug that inhibits the movement of ⁇ TTP to the cell membrane and inhibits the release of ⁇ -tocopherol from the cell membrane into the blood Is mentioned.
  • ⁇ -Tocopherol Absorption Inhibitor ⁇ -Tocopherol is absorbed from the small intestine as a food component, but a drug that suppresses uptake from the small intestine has the effect of reducing the blood concentration of ⁇ -tocopherol.
  • examples of such drugs include the following I) to III).
  • LPL Lipoprotein lipase inhibitor Triton WR1339 etc.
  • cytochrome P450 CYP4F2, CYP4F3, etc.
  • Drugs that promote metabolism and ⁇ -oxidation by cytochrome P450 may reduce ⁇ -tocopherol blood levels.
  • Cytochrome P450 CYP4F2
  • RXR nuclear receptor retinoid X receptor
  • SREBP sterol regulatory element-binding protein
  • the present invention further provides a screening method for a preventive or therapeutic agent for malaria.
  • ⁇ -tocopherol release assay (FIGS. 1 to 3) Liposomes containing tritium-labeled ([ 3 H]) tocopherol acetate ([ 3 H] ⁇ -TocAc) are prepared and added to the medium. [ 3 H] ⁇ -TocAc is rapidly taken up into the cell, and the acetate is removed by non-specific hydrolase to form tritium-labeled ⁇ -Toc ([ 3 H] ⁇ -Toc), which is extracellularly released. Released. 24 hours after the addition of liposomes, the cells and the medium were separately collected, lipids were extracted, developed by thin layer liquid chromatography (using chloroform), and exposed. In addition tocopherol acetate, ⁇ -tocopherol can be used similarly, but tocopherol acetate is preferred.
  • Any label other than the tritium label ([ 3 H]) can be used as long as it does not substantially affect the intracellular uptake and release of ⁇ -tocopherol or its ester.
  • ⁇ -TocAc and ⁇ -Toc in the cell and in the medium can be quantified separately (FIG. 2).
  • McA-TTP21 cells mean hepatocytes with ⁇ TTP
  • McA-RH7777 cells mean hepatocytes without ⁇ TTP.
  • Arita M, Nomura K, Arai H, Inoue K. alpha-tocopherol transfer protein stimulates the secretion of alpha-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway.
  • Liposome composition Phospholipid (phosphatidylcholine, phosphatidylserine, dicetyl phosphate mixture) 200 ⁇ l Cholesterol (3mM) 100 ⁇ l [ 3 H] ⁇ -TocAc (11,100,000 dpm) 300 ⁇ l Unlabeled ⁇ -TocAc 10 ⁇ l
  • the solvent (chloroform) of the mixture of the above reagents is completely dried using nitrogen gas. Add 200 ⁇ l of 0.3M glucose solution and treat with an ultrasonic crusher for 3 minutes.
  • the chloroform layer is transferred to another tube, concentrated as necessary, and then measured by HPLC-ECD.
  • a method using ⁇ -tocopherol measurement by a mass spectrometer A method using a mass spectrometer (GC-MS or LC-MS) as a method to add ⁇ -tocopherol acetate to cells and measure the ⁇ -tocopherol content in the medium and in the same manner as in I) above. It can be used in the screening method of the invention.
  • a mass spectrometer GC-MS or LC-MS
  • V Fluorescence microscopic observation of the localization of ⁇ TTP in cells If ⁇ TTP bound to ⁇ -tocopherol moves within the cell and does not pass to transporters such as ABCA1, it is distributed into the circulating blood from the liver cells. Not. Accordingly, if a drug that inhibits intracellular movement of ⁇ TTP is screened, a candidate for a blood concentration inhibitor of ⁇ -tocopherol can be selected. In particular, (i) Cells expressing ⁇ TTP such as McA-TTP cells are used. (ii) Stop the reaction over time after administration of the test drug. Wash cells with PBS and fix with paraformaldehyde.
  • Intracellularly localized ⁇ TTP is fractionated and purified for each organelle (using density gradient centrifugation using density gradients such as sucrose and ficoll and cell fraction purification kit)
  • the ratio of ⁇ TTP and the amount of ⁇ TTP protein in each organelle are analyzed by Western blotting using an anti- ⁇ TTP-specific antibody or ELISA quantification.
  • the present invention further includes a method for treating or preventing malaria, the method for preventing or treating malaria, comprising administering an effective amount of a compound that decreases the blood concentration of ⁇ -tocopherol to a patient in need of treatment or prevention of malaria. Also provided is the use of a compound that decreases the blood concentration of ⁇ -tocopherol for the manufacture of a medicament, and a compound that decreases the blood concentration of ⁇ -tocopherol for use as a prophylactic or therapeutic agent for malaria.
  • the compound that reduces the blood concentration of ⁇ -tocopherol and the effective amount thereof are as described above.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound that significantly reduces the blood concentration of ⁇ -tocopherol and a pharmaceutically acceptable carrier.
  • These pharmaceutical compositions can be used for the treatment or prevention of malaria.
  • the pharmaceutical composition can be used for oral, parenteral or topical administration. These are, for example, orally, for example in the form of tablets, coated tablets, hard and soft capsules, solutions, emulsions or suspensions, nasally, for example in the form of a spray, rectally, for example in the form of a suppository. It can be administered parenterally, for example in the form of injection solutions or infusions, or topically, for example in the form of ointments, creams or lotions.
  • Normal diet 75 mg ⁇ -tocopherol per kg of food
  • Probucol diet 75 mg ⁇ -tocopherol and 10 g of probucol per kg of diet (1% w / w)
  • Example 1 Six groups (three males and three females) of each group of 4-week-old C57BL / 6J mice were used, and the probucol diet was given for 2 weeks before changing to a normal diet.
  • Plasma component was separated by centrifugation at 3500 rpm for 5 minutes. Three times the amount of 20 ⁇ M BHT-containing chloroform / methanol (2/1) was added to the plasma, and the mixture was shaken and mixed for 1 minute, and then centrifuged at 15,000 rpm for 5 minutes.
  • the chloroform layer was transferred to another tube, and the ⁇ -tocopherol concentration in plasma was measured by HPLC-ECD.
  • 0w, 1w, and 2w indicate the number of weeks after the end of probucol administration.
  • the blood concentration of ⁇ -tocopherol decreased to 0.078 ⁇ M for males and 0.132 ⁇ M for females.
  • the blood levels rose again 0.3 weeks, with 0.334 ⁇ M for males and 0.533 ⁇ M for females after 2 weeks, and 0.847 ⁇ M for males and 0.544 ⁇ M for females after 2 weeks.
  • probucol can significantly reduce the ⁇ -tocopherol concentration in plasma by oral administration.
  • the ⁇ -tocopherol concentration in plasma recovers greatly in 2 weeks, so that the side effects are estimated to be low.
  • Example 2 A malaria parasite infection experiment was carried out using 6 mice (3 males and 3 females) in each group of C57BL / 6J mice aged 4 weeks.
  • mice fed the normal diet The group of C57BL / 6J mice fed the normal diet and the group of ⁇ TTP KO mice fed the normal diet were infected with malaria parasites.
  • the administration of the probucol diet was started 2 weeks before the infection, and the group of C57BL / 6J mice that continued to receive the probucol diet after the infection were compared with the above two groups.
  • the normal meal and probucol meal were the same as described above (FIGS. 5A to 5C).
  • the infected malaria parasite was the murine malaria parasite Plasmodium.yoelii 17XL, and a red blood cell solution containing 1 ⁇ 10 5 cells per ml of the red blood cells parasitized with the malaria parasite was intraperitoneally administered (0.2 ⁇ 10 5 infected red blood cells).
  • Measure the protozoa infection rate by measuring the number of erythrocytes infected with protozoa and the number of non-infected erythrocytes under a microscope.
  • the protozoal infection rate increased transiently from the 6th day to the 12th day after the infection. The rate was 0. In the group receiving probucol, the mortality rate was significantly reduced, with only a few deaths on the 28th day.
  • Example 3 In the same manner as in Example 2 described above, the mice were fed with a normal diet or probucol and were infected with malaria parasites. However, in the probucol administration group, the diet was changed to the normal diet 30 days after infection (FIG. 6A).
  • the malaria parasite infection method, evaluation items, and evaluation method are the same as in the experiment of Example 2.

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PCT/JP2013/051829 2012-02-08 2013-01-29 Médicament destiné à prévenir ou à traiter la malaria et procédé de criblage permettant de l'identifier Ceased WO2013118606A1 (fr)

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JPWO2023063284A1 (fr) * 2021-10-11 2023-04-20

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Cited By (2)

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JPWO2023063284A1 (fr) * 2021-10-11 2023-04-20
WO2023063284A1 (fr) * 2021-10-11 2023-04-20 テオリアサイエンス株式会社 Amplificateur de sécrétion de vésicules extracellulaires pour amplifier la sécrétion de vésicule extracellulaire, et son utilisation

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