JPH1072355A - Adsorption inhibitor for influenza virus - Google Patents
Adsorption inhibitor for influenza virusInfo
- Publication number
- JPH1072355A JPH1072355A JP8247096A JP24709696A JPH1072355A JP H1072355 A JPH1072355 A JP H1072355A JP 8247096 A JP8247096 A JP 8247096A JP 24709696 A JP24709696 A JP 24709696A JP H1072355 A JPH1072355 A JP H1072355A
- Authority
- JP
- Japan
- Prior art keywords
- influenza virus
- sulfatide
- adsorption inhibitor
- solution
- ganglioside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 241000712461 unidentified influenza virus Species 0.000 title claims abstract description 49
- 238000001179 sorption measurement Methods 0.000 title claims abstract description 15
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 208000015181 infectious disease Diseases 0.000 abstract description 5
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical class O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 abstract description 3
- 102000018265 Virus Receptors Human genes 0.000 abstract description 2
- 108010066342 Virus Receptors Proteins 0.000 abstract description 2
- 150000002270 gangliosides Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OWMXULOUTAAVIX-HNZIOFRCSA-N (2s,4r,5s,6s)-5-acetamido-2-[(2r,3r,4s,5s,6r)-2-[(2s,3r,4r,5r,6r)-3-acetamido-2-[(2s,3r,4s,5s,6r)-2-[(2r,3s,4r,5r,6r)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(z)-3-hydroxy-2-(octadecanoylamino)octadec-4-enoxy]oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4 Chemical compound O[C@@H]1[C@@H](O)[C@H](OCC(NC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C/CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@]4(O[C@@H]([C@@H](NC(C)=O)[C@H](O)C4)C(O)C(O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](O)[C@@H](CO)O1 OWMXULOUTAAVIX-HNZIOFRCSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241001500351 Influenzavirus A Species 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000185 hemagglutinin Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- 102000005348 Neuraminidase Human genes 0.000 description 3
- 108010006232 Neuraminidase Proteins 0.000 description 3
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
- 101710176177 Protein A56 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108060003393 Granulin Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000011931 Nucleoproteins Human genes 0.000 description 2
- 108010061100 Nucleoproteins Proteins 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000004884 grey matter Anatomy 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- LVSPDZAGCBEQAV-UHFFFAOYSA-N 4-chloronaphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=C(Cl)C2=C1 LVSPDZAGCBEQAV-UHFFFAOYSA-N 0.000 description 1
- 101710125089 Bindin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 239000012614 Q-Sepharose Substances 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 235000021310 complex sugar Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- -1 pessaries Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、インフルエンザウ
イルス吸着阻止剤に関する。本発明のインフルエンザウ
イルス吸着阻止剤によるとインフルエンザウイルスの細
胞への吸着を阻止し、感染を防御することができる。The present invention relates to an influenza virus adsorption inhibitor. According to the influenza virus adsorption inhibitor of the present invention, adsorption of influenza virus to cells can be prevented, and infection can be prevented.
【０００２】[0002]
【従来の技術】インフルエンザウイルスはオルソミクソ
ウイルス科に属するウイルスで、その粒子は直径80〜10
0nm の球形状であり、宿主由来の脂質二重膜を有するい
わゆるエンベロープウイルスの一種である。そして、イ
ンフルエンザウイルスのエンベロープ外側は、三量体を
形成したヘマグルチニン (赤血球凝集素) と四量体を形
成したノイラミニダーゼの二種類の糖タンパク質がスパ
イク状に突き出した形状を呈している。また、インフル
エンザウイルスの粒子内部は、 (−) 鎖ＲＮＡ、核タン
パク質及び３種のＲＮＡポリメラーゼからなる８本の分
節を形成したリボヌクレオプロテインとマトリクスプロ
テインとが存在しており、主に、このリボヌクレオプロ
テインとマトリクスプロテインの抗原性の差により、イ
ンフルエンザウイルスはＡ型、Ｂ型及びＣ型に分類され
ている。さらに、Ａ型は、ヘマグルチニンとノイラミニ
ダーゼの抗原性の差により、多くの亜型(subtype) に分
類されている。現在、ヘマグルチニンは14種 (Ｈ１〜Ｈ
14) 、ノイラミニダーゼは９種 (Ｎ１〜Ｎ９) が知られ
ている。なお、インフルエンザウイルスの細胞への感染
は、インフルエンザウイルスが宿主細胞の表面に存在す
るレセプター糖鎖 (シアロ複合糖鎖) にヘマグルチニン
を介して吸着した後、エンドサイトーシスにより細胞内
に取り込まれてエンドソームやライソゾームに運搬さ
れ、顆粒内の弱酸性条件下でウイルス膜とオルガネラ膜
が融合してウイルス粒子内容物を細胞外へ放出するとい
う機構が考えられている。2. Description of the Related Art Influenza virus is a virus belonging to the family Orthomyxoviridae, and its particle size is 80 to 10 in diameter.
It is a type of envelope virus having a spherical shape of 0 nm and having a host-derived lipid bilayer. The outer side of the envelope of the influenza virus has a shape in which two types of glycoproteins, ie, hemagglutinin (haemagglutinin) forming a trimer and neuraminidase forming a tetramer, protrude in a spike shape. Also, inside the particles of influenza virus, ribonucleoproteins and matrix proteins that form eight segments composed of (−)-strand RNA, nucleoprotein, and three types of RNA polymerases are present. Influenza viruses are classified into type A, type B and type C due to the difference in antigenicity between nucleoprotein and matrix protein. In addition, type A is classified into many subtypes due to the difference in antigenicity between hemagglutinin and neuraminidase. At present, there are 14 hemagglutinins (H1-H
14) Nine types of neuraminidase (N1 to N9) are known. Influenza virus is transmitted to cells by influenza virus adsorbing via hemagglutinin to a receptor sugar chain (sialo complex sugar chain) present on the surface of the host cell, and then taken into the cell by endocytosis, resulting in endosomal infection. A mechanism is considered that the virus membrane and the organelle membrane fuse under weakly acidic conditions within the granules and release the contents of the virus particles out of the cell.
【０００３】このインフルエンザウイルスは、未だ有効
な治療法や感染防御法が見出されていない病原体の一つ
である。インフルエンザウイルスは、極めて感染性が強
く、抗原変異を繰り返し、それまでの抗原性とは大きく
異なる新種が出現するため、効果的な防御対策が立て難
く、10数年に一度の割合で世界的規模の流行を繰り返し
ている。今世紀に入ってもスペイン風邪をはじめとし
て、アジア風邪、ホンコン風邪、ソ連風邪等が出現し、
多数の人命を脅かしてきている。このような背景から、
インフルエンザウイルス感染の予防や治療効果を有する
医薬の開発が待たれている現状にある。[0003] This influenza virus is one of the pathogens for which no effective treatment method or infection protection method has yet been found. The influenza virus is extremely infectious, repeats antigenic mutation, and a new species that differs significantly from the previous antigenicity appears, making it difficult to establish effective protective measures. The trend is repeating. Even in this century, Spanish cold, Asian cold, Hong Kong cold, Soviet cold etc appeared,
It has threatened many lives. Against this background,
There is a need for the development of medicines that have the effect of preventing and treating influenza virus infection.
【０００４】[0004]
【発明が解決しようとする課題】本発明者らは、インフ
ルエンザウイルス感染の予防や治療効果を有する物質を
求めて鋭意研究を進めていたところ、インフルエンザウ
イルスの受容体機能を有することが知られているガング
リオシド (ＧＤｌａ等) とは異なるシアロ糖鎖を含まな
い硫酸化糖脂質のスルファチドが、インフルエンザウイ
ルスとの強い結合活性を有することを見出し、本発明を
完成するに至った。したがって、本発明は、新規なイン
フルエンザウイルス吸着阻止剤を提供することを課題と
する。さらに詳細には、スルファチドを有効成分とする
新規なインフルエンザウイルス吸着阻止剤を提供するこ
とを課題とする。DISCLOSURE OF THE INVENTION The present inventors have intensively studied for a substance having a prophylactic or therapeutic effect on influenza virus infection. As a result, it has been known that the substance has an influenza virus receptor function. The present inventors have found that sulfatide, a sulfated glycolipid containing no sialo-glycan different from gangliosides (GDla and the like), has a strong binding activity to influenza virus, and completed the present invention. Therefore, an object of the present invention is to provide a novel influenza virus adsorption inhibitor. More specifically, an object of the present invention is to provide a novel influenza virus adsorption inhibitor containing sulfatide as an active ingredient.
【０００５】[0005]
【課題を解決するための手段】本発明は、スルファチド
を有効成分とするインフルエンザウイルス吸着阻止剤に
関する。本発明のインフルエンザウイルス吸着阻止剤の
有効成分として使用するスルファチドは、下記の一般式
（Ｉ）で示される既知の糖脂質であり、脳灰白質に比較
的多量に存在することが知られている物質である。The present invention relates to an influenza virus adsorption inhibitor containing sulfatide as an active ingredient. Sulfatide used as an active ingredient of the influenza virus adsorption inhibitor of the present invention is a known glycolipid represented by the following general formula (I) and is known to be present in a relatively large amount in brain gray matter. Substance.
【０００６】[0006]
【化１】 Embedded image
【０００７】なお、スルファチドの製造方法としては、
例えば、牛脳から抽出精製する方法(Lipids, vol.20, p
p.588-598,1985; 生化学実験講座「脂質の科学」, vol.
3, pp.368-388,東京化学同人発行) や化学合成する方法
(Carbohydrate Res., vol.2,pp.371-379, 1966)等が知
られている。また、スルファチドは、試薬として市販も
されている。The method for producing sulfatide includes the following:
For example, a method of extracting and purifying from bovine brain (Lipids, vol. 20, p.
p.588-598,1985; Laboratory of Biochemistry "Science of Lipids", vol.
3, pp.368-388, published by Tokyo Chemical Doujinshi)
(Carbohydrate Res., Vol. 2, pp. 371-379, 1966) and the like. Sulfatide is also commercially available as a reagent.
【０００８】以下に、参考例として、スルファチドの調
製方法を示す。Hereinafter, a method for preparing sulfatide will be described as a reference example.
【参考例１】新鮮なウシ脳灰白質１kgに５倍量のアセト
ンを加えてホモジナイズした後、濾過して抽出液を得
た。この抽出液を凍結乾燥した後、５倍量のクロロホル
ム：メタノール＝２：１(v/v) 溶媒で抽出し、さらに、
クロロホルム：メタノール＝１：１(v/v) 溶媒で抽出し
て濃縮して濃縮液を得た。次に、この濃縮液を３倍量の
アセトンで抽出した後、３倍量のジエチルエーテルで処
理してグリセロホスホリピドを除去した。そして、0.5N
水酸化ナトリウム／メタノール溶液で37℃、３時間処理
し、蒸留水に透析した後、凍結乾燥してスルファチドの
粗画分を得た。このスルファチドの粗画分をフォルチ分
配法(Folchs partition)に供して下層を集めた後、クロ
ロホルム：メタノール：水＝30：60：８(v/v/v) 溶媒で
平衡化したＱ−セファロースカラムに供し、酢酸ナトリ
ウム０〜4Mの直線グラジエントで溶出した。そして、各
溶出画分を薄層クロマトグラフに供してスルファチド標
準物質と比較確認した。その結果、スルファチドは、酢
酸ナトリウム１〜1.5Mの溶出画分に溶出されていること
が判った。この溶出画分をエバポレートして溶媒を除去
した後、残渣に蒸留水を加えて溶解し、蒸留水に対して
透析した後、凍結乾燥して純度99％以上のスルファチド
の白色粉末を得た。[Reference Example 1] A 5-fold amount of acetone was added to 1 kg of fresh bovine brain gray matter, homogenized, and filtered to obtain an extract. After freeze-drying this extract, extraction was performed with a 5-fold amount of chloroform: methanol = 2: 1 (v / v) solvent.
Extraction with a chloroform: methanol = 1: 1 (v / v) solvent and concentration gave a concentrated solution. Next, the concentrated solution was extracted with a three-fold amount of acetone, and then treated with a three-fold amount of diethyl ether to remove glycerophospholipid. And 0.5N
The mixture was treated with a sodium hydroxide / methanol solution at 37 ° C. for 3 hours, dialyzed against distilled water, and lyophilized to obtain a crude sulfatide fraction. The crude fraction of this sulfatide was subjected to a Folchs partition method to collect the lower layer, and then a Q-Sepharose column equilibrated with a chloroform: methanol: water = 30: 60: 8 (v / v / v) solvent. And eluted with a linear gradient of 0-4M sodium acetate. Each eluted fraction was subjected to thin-layer chromatography, and compared with a sulfatide standard substance and confirmed. As a result, it was found that sulfatide was eluted in the elution fraction of 1 to 1.5 M sodium acetate. The eluted fraction was evaporated to remove the solvent, and the residue was dissolved by adding distilled water, dialyzed against distilled water, and freeze-dried to obtain a white powder of sulfatide having a purity of 99% or more.
【０００９】本発明は、このようなスルファチドを有効
成分とするインフルエンザウイルス吸着阻止剤を投与す
ることによって組織へのインフルエンザウイルスの吸着
を阻止し、インフルエンザウイルスの感染を防御しよう
とするものである。The present invention aims to prevent influenza virus infection by preventing the influenza virus from adsorbing to tissues by administering such an influenza virus adsorption inhibitor containing sulfatide as an active ingredient.
【００１０】次に、スルファチドのインフルエンザウイ
ルスに対する効果を確認した試験例を示す。Next, test examples in which the effect of sulfatide on influenza virus was confirmed will be described.
【試験例１】参考例１で得られたスルファチドと、イン
フルエンザウイルスに強く結合することが知られている
シアリルパラグロボシドとを使用し、TLC/Virus Bindin
g Assay によりインフルエンザウイルスに対する反応性
を調べた。すなわち、シリカゲル薄層板(Polygram Sil
G Nagel)上に、0.25〜1.50nmolのスルファチド又はシア
リルパラグロボシドをスポットし、クロロホルム：メタ
ノール：水＝５：４：１(v/v/v) 溶媒で展開した後、風
乾し、１％ウシ血清アルブミン- リン酸緩衝液(ＢＳＡ
−ＰＢＳ) 溶液で４℃、一晩処理した。このシリカゲル
薄層板をＰＢＳ溶液で５回洗浄した後、インフルエンザ
ウイルスA/Aichi/2/68(H3N2)−ＰＢＳ懸濁液を加えて、
４℃、一晩振盪した。その後、ＰＢＳ溶液で５回洗浄し
た後、１％ＢＳＡ−ＰＢＳ溶液で 250倍に希釈した抗イ
ンフルエンザウイルス抗体と、４℃、３時間反応させ
た。なお、抗インフルエンザウイルス抗体は、インフル
エンザウイルスA/Aichi/2/68(H3N2)をウサギに免疫する
ことにより得られたポリクローナル抗体を使用した。こ
のシリカゲル薄層板をＰＢＳ溶液で５回洗浄した後、25
0倍に希釈した西洋ワサビペルオキシダーゼ標識プロテ
インＡを含む１％ＢＳＡ−ＰＢＳ溶液中で、４℃、３時
間反応させた。このシリカゲル薄層板をＰＢＳ溶液で５
回洗浄した後、0.1M酢酸緩衝液(pH 6.0) 10ml に、110m
M 4-クロロ-1-ナフトールを含むアセトニトリル溶液 20
0μl 、 60mM N,N-ジエチル -p-フェニルエジアミン-
ジヒドロキシクロライドを含むアセトニトリル溶液 200
μl 及び30％過酸化水素水１μl を混和した発色液を加
えて、室温で15分間振盪反応させた。このシリカゲル薄
層板を精製水で洗浄した後、風乾し、発色をデンシトメ
ーター(CS-9000、島津製作所) により、測定波長 600n
m、対照波長 425nmにて定量した。その結果を図１に示
す。図１に示すようにスルファチド（○）はシアリルパ
ラグロボシド（●）にくらべてインフルエンザウイルス
に対して高い反応性を示している。すなわち、スルファ
チドは、インフルエンザウイルスに強く結合することが
知られているシアリルパラグロボシドよりもさらに強く
インフルエンザウイルスと濃度依存的に結合することが
判った。[Test Example 1] TLC / Virus Bindin using the sulfatide obtained in Reference Example 1 and sialyl paragloboside known to strongly bind to influenza virus
g Assay was used to determine reactivity to influenza virus. That is, a silica gel thin plate (Polygram Sil
G Nagel), spot 0.25 to 1.50 nmol of sulfatide or sialyl paragloboside, develop with chloroform: methanol: water = 5: 4: 1 (v / v / v) solvent, air-dry and 1% Bovine serum albumin-phosphate buffer (BSA
-PBS) solution at 4 ° C overnight. After washing this silica gel thin plate five times with a PBS solution, an influenza virus A / Aichi / 2/68 (H3N2) -PBS suspension was added,
Shake at 4 ° C. overnight. Thereafter, the plate was washed five times with a PBS solution, and reacted with an anti-influenza virus antibody diluted 250 times with a 1% BSA-PBS solution at 4 ° C. for 3 hours. As the anti-influenza virus antibody, a polyclonal antibody obtained by immunizing rabbits with influenza virus A / Aichi / 2/68 (H3N2) was used. After washing this silica gel thin plate five times with a PBS solution,
Reaction was carried out at 4 ° C. for 3 hours in a 1% BSA-PBS solution containing horseradish peroxidase-labeled protein A diluted to 1: 0. This silica gel thin plate is
After washing 10 times, add 10 ml of 0.1 M acetate buffer (pH 6.0) to 10 ml.
M Acetonitrile solution containing 4-chloro-1-naphthol 20
0 μl, 60 mM N, N-diethyl-p-phenylediamine-
Acetonitrile solution containing dihydroxy chloride 200
A color developing solution mixed with 1 μl of 30% hydrogen peroxide and 1 μl of 30% aqueous hydrogen peroxide was added, and the mixture was shaken at room temperature for 15 minutes. After washing the silica gel thin plate with purified water, air-dry it and measure the color with a densitometer (CS-9000, Shimadzu Corporation) at a measurement wavelength of 600 n.
m, quantified at a control wavelength of 425 nm. The result is shown in FIG. As shown in FIG. 1, sulfatide (○) shows higher reactivity to influenza virus than sialyl paragloboside (●). That is, it was found that sulfatide binds more strongly to influenza virus in a concentration-dependent manner than sialyl paragloboside, which is known to bind strongly to influenza virus.
【００１１】[0011]
【試験例２】参考例１で得られたスルファチドとガング
リオシドＧＭ３を使用し、 ELISA法(Enzyme-Linked Imm
uno Sorbent Assay)によりインフルエンザウイルスに対
する反応性を調べた。すなわち、マイクロプレート(96f
lat-bottom wells, PolysorpNunc.) の各ウエルに、エ
タノールに溶解した４〜500pmol 濃度のスルファチド又
はガングリオシドＧＭ３を50μl ずつ加え、37℃でエタ
ノールを完全に蒸発させた後、１％ＢＳＡ−ＰＢＳを 2
00μl ずつ加え、一晩ブロッキングした。各ウエルをＰ
ＢＳ溶液で５回洗浄した後、インフルエンザウイルスA/
Aichi/2/68を含む 0.5％ＢＳＡ−ＰＢＳ懸濁液(32HAU)
を各ウエルに50μl ずつ加え、４℃、一晩振盪した。各
ウエルをＰＢＳ溶液で５回洗浄し、 1,000倍希釈した抗
インフルエンザウイルス抗体を含む 0.5％ＢＳＡ−ＰＢ
Ｓを各ウエルに50μl ずつ加え、４℃、２時間反応させ
た。各ウエルをＰＢＳ溶液で５回洗浄した後、 0.5％Ｂ
ＳＡ−ＰＢＳ溶液で 1,000倍希釈した西洋ワサビペルオ
キシダーゼ標識Protein Aを50μl ずつ加え、４℃、２
時間反応させた。各ウエルをＰＢＳ溶液で４回洗浄した
後、発色基質溶液（オルトフェニレンジアミン４mgをク
エン酸−リン酸緩衝液(pH5.6) 10mlに溶解し、30％過酸
化水素 3.3μl を加えた溶液)100μl を加えて暗所発色
させた後、1N塩酸 100μl を加えて反応を停止させて、
マイクロプレートリーダー (CORONA、MTP-32) により、
測定波長 496nm、対照波長 630nmにて比色定量した。そ
の結果を図２に示す。図２にみられるようにスルファチ
ド（○）は、ガングリオシドＧＭ３（●）よりも強くイ
ンフルエンザウイルスと結合することが判った。[Test Example 2] Using the sulfatide and ganglioside GM3 obtained in Reference Example 1, an ELISA method (Enzyme-Linked Imm
uno Sorbent Assay) was used to examine reactivity to influenza virus. That is, the microplate (96f
lat-bottom wells, Polysorp Nunc.), 50 μl of 4-500 pmol of sulfatide or ganglioside GM3 dissolved in ethanol was added to each well, and the ethanol was completely evaporated at 37 ° C., and 1% BSA-PBS was added to 2 wells.
The solution was added in an amount of 00 μl each and blocked overnight. P each well
After washing 5 times with a BS solution, the influenza virus A /
0.5% BSA-PBS suspension containing Aichi / 2/68 (32HAU)
Was added to each well in an amount of 50 μl, and the mixture was shaken at 4 ° C. overnight. Each well was washed 5 times with a PBS solution, and 0.5% BSA-PB containing an anti-influenza virus antibody diluted 1,000 times.
50 μl of S was added to each well, and the mixture was reacted at 4 ° C. for 2 hours. After washing each well 5 times with a PBS solution, 0.5% B
Horseradish peroxidase-labeled Protein A diluted 1,000 times with SA-PBS solution was added in 50 μl portions at 4 ° C.
Allowed to react for hours. After washing each well four times with a PBS solution, a chromogenic substrate solution (a solution obtained by dissolving 4 mg of orthophenylenediamine in 10 ml of a citrate-phosphate buffer (pH 5.6) and adding 3.3 μl of 30% hydrogen peroxide) After adding 100 μl to develop color in the dark, the reaction was stopped by adding 100 μl of 1N hydrochloric acid.
Microplate reader (CORONA, MTP-32)
Colorimetry was performed at a measurement wavelength of 496 nm and a control wavelength of 630 nm. The result is shown in FIG. As shown in FIG. 2, sulfatide (ス ル) was found to bind more strongly to influenza virus than ganglioside GM3 (●).
【００１２】[0012]
【試験例３】参考例１で得られたスルファチドとガング
リオシドＧＭ３を使用し、溶血活性阻害実験によりイン
フルエンザウイルスに対する反応性を調べた。すなわ
ち、スルファチド又はガングリオシドＧＭ３をＰＢＳに
溶解した後、512HAUのインフルエンザウイルスA/Aichi/
2/68を加えて、４℃、３時間反応させた溶液50μl を２
％ニワトリ赤血球１mlに加え、４℃、30分反応させた。
そして、生理的食塩水で３回遠心洗浄(1,200×g)した
後、50mM酢酸等張緩衝液(pH5) １mlを加えて、37℃、30
分間反応させた。氷冷して反応を停止し、遠心(1,200×
g)した後、波長 540nmにて上清中のヘモグロビン量を測
定した。その結果を図３に示す。図３にみられるように
ガングリオシドＧＭ３（●）は、インフルエンザウイル
スによる赤血球の溶血作用を阻害する活性を殆ど有さな
かったが、スルファチド（○）は、インフルエンザウイ
ルスによる赤血球の溶血作用を阻害する活性を有してい
ることが判った。[Test Example 3] Using the sulfatide obtained in Reference Example 1 and ganglioside GM3, the reactivity to influenza virus was examined by a hemolytic activity inhibition experiment. That is, after dissolving sulfatide or ganglioside GM3 in PBS, 512 HAU of influenza virus A / Aichi /
2/68 was added, and 50 µl of the solution reacted at 4 ° C for 3 hours was added to 2/68.
% Chicken erythrocytes (1 ml) and reacted at 4 ° C. for 30 minutes.
After centrifugal washing (1,200 × g) three times with physiological saline, 1 ml of 50 mM acetic acid isotonic buffer (pH 5) was added, and the mixture was added at 37 ° C. and 30 ° C.
Allowed to react for minutes. Stop the reaction by cooling on ice and centrifuge (1,200 x
g) After that, the amount of hemoglobin in the supernatant was measured at a wavelength of 540 nm. The result is shown in FIG. As can be seen in FIG. 3, ganglioside GM3 (●) had almost no activity to inhibit the erythrocyte hemolysis by influenza virus, whereas sulfatide (O) showed the activity to inhibit erythrocyte hemolysis by influenza virus. It was found to have.
【００１３】[0013]
【発明の実施の形態】本発明のインフルエンザウイルス
吸着阻止剤は、スルファチドを有効成分とするものであ
り、インフルエンザウイルスの細胞への吸着を阻止する
目的で使用される。スルファチドは、脳のミエリン構成
物質であって毒性が殆どないので、投与方法に特に制限
はなく、軟カプセル剤、硬カプセル剤、錠剤、丸剤、顆
粒剤、懸濁剤、散剤、液剤、シロップ剤、乳濁剤、エリ
キシル剤等の経口剤、注射剤、ペッサリー、坐剤、軟
膏、塗布剤等の非経口剤として投与することができる。
なお、一日当たり成人の投与量は、経口投与で約 0.1〜
1g、静脈内投与で約10〜100mg、筋肉内投与で約50〜300
mg 、皮下及び皮内投与で約30〜150mg が好ましく、一
日一回又は数回に分けて投与すれば良い。BEST MODE FOR CARRYING OUT THE INVENTION The influenza virus adsorption inhibitor of the present invention contains sulfatide as an active ingredient and is used for the purpose of inhibiting the adsorption of influenza virus to cells. Sulfatide is a brain myelin constituent and has almost no toxicity, so there is no particular limitation on the administration method, and soft capsules, hard capsules, tablets, pills, granules, suspensions, powders, solutions, syrups Preparations, emulsions, elixirs and other oral preparations, parenteral preparations such as injections, pessaries, suppositories, ointments and liniments.
The daily dose for adults is about 0.1-
1 g, about 10-100 mg by intravenous administration, about 50-300 by intramuscular administration
mg, preferably about 30 to 150 mg for subcutaneous and intradermal administration, and may be administered once or several times a day.
【００１４】本発明の製剤例を実施例として示す。本発
明は、これらの実施例にのみ限定して解釈されるべきも
のではない。The preparation examples of the present invention are shown as working examples. The present invention should not be construed as being limited to only these examples.
【実施例１】参考例１で得られたスルファチド10g を精
製蒸留水1Lに懸濁し、これを10mLのアンプルに充填し、
殺菌を行なって静注用注射剤を得た。Example 1 10 g of the sulfatide obtained in Reference Example 1 was suspended in 1 L of purified distilled water, and the suspension was filled in a 10 mL ampoule.
Sterilization was performed to obtain an injection for intravenous injection.
【００１５】[0015]
【実施例２】参考例１で得られたスルファチド200gを乳
糖15g 、トウモロコシ澱粉15g 、カルボキシメチルセル
ロースカルシウム10g 及びステアリン酸マグネシウム1
g を混合し、打錠して錠剤1000錠を製造した。Example 2 200 g of the sulfatide obtained in Reference Example 1 was lactose 15 g, corn starch 15 g, carboxymethylcellulose calcium 10 g and magnesium stearate 1 g.
g were mixed and tabletted to produce 1000 tablets.
【００１６】[0016]
【発明の効果】スルファチドは、インフルエンザウイル
スと強く結合するので、インフルエンザウイルスの吸着
を阻止することができる。したがって、本発明のスルフ
ァチドを有効成分とするインフルエンザウイルス吸着阻
止剤を使用することにより、インフルエンザウイルスの
感染を予防することができる。Industrial Applicability Since sulfatide strongly binds to influenza virus, it can prevent the influenza virus from being adsorbed. Therefore, influenza virus infection can be prevented by using the influenza virus adsorption inhibitor containing the sulfatide of the present invention as an active ingredient.
【図１】試験例１におけるスルファチドとシアリルパラ
グロボシドのインフルエンザウイルスに対する反応性を
示す。FIG. 1 shows the reactivity of sulfatide and sialyl paragloboside against influenza virus in Test Example 1.
○：スルファチド ●：シアリルパラグロボシド ○: Sulfatide ●: Sialyl paragloboside
【図２】試験例２におけるスルファチドとガングリオシ
ドＧＭ３のインフルエンザウイルスに対する反応性を示
す。FIG. 2 shows the reactivity of sulfatide and ganglioside GM3 against influenza virus in Test Example 2.
○：スルファチド ●：ガングリオシドＧＭ３ ○: Sulfatide ●: Ganglioside GM3
【図３】試験例３におけるスルファチドとガングリオシ
ドＧＭ３のインフルエンザウイルスによる溶血阻止活性
を示す。FIG. 3 shows the inhibitory activity of sulfatide and ganglioside GM3 on influenza virus hemolysis in Test Example 3.
○：スルファチド ●：ガングリオシドＧＭ３ ○: Sulfatide ●: Ganglioside GM3
───────────────────────────────────────────────────── フロントページの続き (72)発明者 鈴木 隆 静岡県清水市折戸519−１ (72)発明者 花形 吾朗 埼玉県狭山市入間川1469−73 (72)発明者 小田 泰士 東京都練馬区関町東１−19−11 イースト パーク202号 (72)発明者 巽 清 埼玉県入間市野田982−２ ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takashi Suzuki 519-1 Orito, Shimizu City, Shizuoka Prefecture (72) Inventor Goro 1469-73, Irumagawa, Sayama City, Saitama Prefecture (72) Inventor Yasushi Oda Sekicho Higashi, Nerima-ku, Tokyo 1-19-11 East Park 202 (72) Inventor Kiyoshi Tatsumi 982-2 Noda, Iruma City, Saitama Prefecture
Claims (1)
エンザウイルス吸着阻止剤。1. An influenza virus adsorption inhibitor comprising sulfatide as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24709696A JP3834362B2 (en) | 1996-08-29 | 1996-08-29 | Influenza virus adsorption inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24709696A JP3834362B2 (en) | 1996-08-29 | 1996-08-29 | Influenza virus adsorption inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1072355A true JPH1072355A (en) | 1998-03-17 |
| JP3834362B2 JP3834362B2 (en) | 2006-10-18 |
Family
ID=17158376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24709696A Expired - Fee Related JP3834362B2 (en) | 1996-08-29 | 1996-08-29 | Influenza virus adsorption inhibitor |
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| Country | Link |
|---|---|
| JP (1) | JP3834362B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233773A (en) * | 2000-02-22 | 2001-08-28 | Toko Yakuhin Kogyo Kk | Antiviral agent |
| WO2005084694A1 (en) * | 2004-03-09 | 2005-09-15 | Glycomedics, Inc. | Influenza virus-infection inhibitor |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021236389A2 (en) * | 2020-05-16 | 2021-11-25 | Bond Jason R | Treatment of known and unknown viral infection with lipid agents |
-
1996
- 1996-08-29 JP JP24709696A patent/JP3834362B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233773A (en) * | 2000-02-22 | 2001-08-28 | Toko Yakuhin Kogyo Kk | Antiviral agent |
| WO2005084694A1 (en) * | 2004-03-09 | 2005-09-15 | Glycomedics, Inc. | Influenza virus-infection inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3834362B2 (en) | 2006-10-18 |
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