WO2022249952A1 - 抗ウイルス剤 - Google Patents

抗ウイルス剤 Download PDF

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Publication number
WO2022249952A1
WO2022249952A1 PCT/JP2022/020679 JP2022020679W WO2022249952A1 WO 2022249952 A1 WO2022249952 A1 WO 2022249952A1 JP 2022020679 W JP2022020679 W JP 2022020679W WO 2022249952 A1 WO2022249952 A1 WO 2022249952A1
Authority
WO
WIPO (PCT)
Prior art keywords
licorice
coronavirus
present
saponin
antiviral agent
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.)
Ceased
Application number
PCT/JP2022/020679
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
正祐 川西
展司 吉川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzuka University Of Medical Science
Cokey Systems Co Ltd
Original Assignee
Suzuka University Of Medical Science
Cokey Systems Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Suzuka University Of Medical Science, Cokey Systems Co Ltd filed Critical Suzuka University Of Medical Science
Priority to JP2023523434A priority Critical patent/JPWO2022249952A1/ja
Publication of WO2022249952A1 publication Critical patent/WO2022249952A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to anti-coronavirus agents containing licorice-derived saponins or licorice extracts.
  • angiotensin converting enzyme type II which serves as a scaffold for the virus to enter the body via the spike protein present on its surface, has attracted attention.
  • This angiotensin-converting enzyme type II exists in various sites in the body, and is particularly distributed in gastrointestinal mucosal epithelial cells including the oral cavity and pharynx (Non-Patent Document 1). Therefore, viruses taken in through the mouth easily bind to angiotensin convertase type II and enter cells. Therefore, as part of the search for antiviral drugs, drugs that inhibit the binding of this virus to the spike protein and angiotensin-converting enzyme type II have been searched. Under such circumstances, licorice-derived glycyrrhizic acid is already expected to be effective through virtual screening (Non-Patent Document 2).
  • Non-Patent Document 3 In the case of a vaccine, it only protects against infection, but if an antiviral agent with an infection-protecting effect is also found to have a therapeutic effect, it goes without saying that its usefulness will be further enhanced.
  • An object of the present invention is to provide an anti-coronavirus agent that effectively prevents infection by coronaviruses such as the novel coronavirus SARS-CoV-2.
  • the present inventors conducted intensive research on the binding inhibitory activity of individual saponins derived from licorice, including glycyrrhizic acid, between the virus and human angiotensin converting enzyme type II.
  • Glycyrrhizic acid was confirmed to have inhibitory activity, and licorice saponin H2, whose sapogenin is liquiritic acid, a stereoisomer of glycyrrhizic acid, inhibits the binding of the virus to human angiotensin-converting enzyme type II more strongly than glycyrrhizic acid.
  • the present invention was completed based on this finding. That is, the present invention is as follows.
  • Formula (1) An antiviral agent comprising at least one selected from the group consisting of a compound represented by, salts thereof, and solvates thereof, and having an infection-preventing action that inhibits the binding of viruses to angiotensin convertase type II. .
  • the antiviral agent of [1] which is used for human application.
  • An antiviral agent comprising a licorice extract containing 5 to 50% of the compound represented by Formula 1 and inhibiting binding of virus to angiotensin converting enzyme type II.
  • the antiviral agent of [4] which is used for human application.
  • the antiviral agent of the present invention is more safe for living organisms and can prevent infection by coronaviruses such as the new coronavirus SARS-CoV-2.
  • licorice saponin H2 is a plant-derived saponin belonging to the genus Glycyrrhiza, and its IUPAC name is (2S,3S,4S,5R,6R)-6- ⁇ [(3S,4aR,6aR , 6bS, 8aS, 11R, 12aR, 14aR, 14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5, 6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl]oxy ⁇ -5- ⁇ [(2R,3R,4S ,5S,6S)-6-Carboxy-3,4,5-trihydroxyoxane-2-yl]oxy ⁇ -3,4-dihydroxyoxane-2-carboxylic acid, which has the following structural formula is
  • Glycyrrhiza is a leguminous perennial that grows naturally in the Mediterranean region, Asia Minor, southern Russia, central Asia, northern China, and North America.
  • Glycyrrhiza acanthocarpa G. aspera, G. astragalina, G. bucharica, G. echinata ( Russian daylily), G. eglandulosa, G. foetida, G. foetidissima, G. glabra (Spanish licorice), G. gontscharovii, G.; iconica, G. inflate, G.
  • korshinskyi G.; lepidota (Glycyrrhiza americana), G. pallidiflora, G. squamulosa, G. triphylla, G. uralensis (Glycyrrhiza uralensis), G. yunnanensis, G. inflata (Xinjiang licorice) can be used. These can be used singly or in combination of two or more.
  • the licorice saponin H2 used in the present invention can be extracted, isolated and purified from licorice extract by a general method. That is, a purified product with a purity of 70% or more can be obtained by removing fat-soluble colored components from the licorice extract by synthetic resin column or organic solvent extraction, followed by fractionation and purification by high performance liquid chromatography.
  • a licorice extract when a licorice extract is used, the root and/or stem of the plant can be appropriately processed before use.
  • a commercially available licorice extract may be used, or a licorice extract produced by a method known in the art may also be used.
  • the licorice saponin H2 content of the licorice extract used in the present invention is 5% or more, preferably 10% or more, more preferably 13% or more.
  • the target virus of the agent of the present invention is not particularly limited, but includes, for example, common cold coronavirus known as coronavirus, SARS-CoV virus, SARS-CoV-2, and the like.
  • Applications applied to the living body include, for example, pharmaceuticals and foods.
  • the application target in this case is not particularly limited. Examples include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats and deer.
  • the antiviral agent of the present invention By applying the antiviral agent of the present invention to the living body, it is possible to exhibit a viral infection-protective effect at the site where the active ingredient comes into contact.
  • the form of the agent of the present invention is not particularly limited, and depending on the application of the agent of the present invention, it can take a form commonly used in each application.
  • the angiotensin converting enzyme type II that attaches when infected with a virus is widely distributed in the oral cavity, gastrointestinal tract, alveoli and other mucous membranes. It is desirable to consider that For example, sprays (internal aerosols), eye drops, gels, eye ointments, nose drops, tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly drops, etc.) Formulations suitable for oral ingestion such as are preferably mentioned, and troches capable of retaining the active ingredient in the oral cavity are particularly preferred. In the case of foods, too, it is desirable to take the form of candy or troche tablets, which allow long-term retention in the oral cavity.
  • the dose of licorice saponin H2 of the present invention is 5-10 mg/day/human, preferably 10-15 mg/day/human.
  • the dose of licorice extract is 50-100 mg/day/person, preferably 100-200 mg/day/person. Moreover, in this case, administration is carried out by dividing the above dose between 5 and 10 times a day.
  • the administration period of the licorice saponin H2 or licorice extract of the present invention is any period as long as the desired effects are obtained. In particular, it is desirable to continue when there is a spread of virus infection.
  • the outline of the virus inhibition measurement method for the test substance is as follows. Briefly, ACE2-His was bound on nickel-coated 96-well plates. Next, SARS-CoV-2 Spike-Fc (RBD) and glycyrrhizic acid or licorice saponin H2 as test substances were added and incubated on a plate, and SARS-CoV-2 Spike-Fc (RBD) was added to ACE2-His. combined.
  • an HRP-labeled Anti-Fc antibody was added to the plate, a chemiluminescent substrate for HRP was added, and the amount of luminescence was measured to determine the interaction between ACE2-His and SARS-CoV-2 Spike-Fc (RBD) and The inhibitory effect of test substances was determined.
  • the antiviral agent of the present invention is useful for protecting against coronavirus infections such as COVID-19.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Mycology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Plant Substances (AREA)
PCT/JP2022/020679 2021-05-25 2022-05-18 抗ウイルス剤 Ceased WO2022249952A1 (ja)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2023523434A JPWO2022249952A1 (https=) 2021-05-25 2022-05-18

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-087620 2021-05-25
JP2021087620 2021-05-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009203182A (ja) * 2008-02-27 2009-09-10 Pola Chem Ind Inc ヒアルロニダーゼ阻害剤及びそれを含有する組成物
JP2019066291A (ja) * 2017-09-29 2019-04-25 丸善製薬株式会社 カンゾウの植物種の同定方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009203182A (ja) * 2008-02-27 2009-09-10 Pola Chem Ind Inc ヒアルロニダーゼ阻害剤及びそれを含有する組成物
JP2019066291A (ja) * 2017-09-29 2019-04-25 丸善製薬株式会社 カンゾウの植物種の同定方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GOMAA ADEL A., ABDEL-WADOOD YASMIN A.: "The potential of glycyrrhizin and licorice extract in combating COVID-19 and associated conditions", PHYTOMEDICINE PLUS, vol. 1, no. 3, 1 August 2021 (2021-08-01), pages 100043, XP093007353, ISSN: 2667-0313, DOI: 10.1016/j.phyplu.2021.100043 *
LIU AILIN, GUAN-HUA DU: "Drug discovery for COVID-19 treatment based on drug targets", ACTA PHARMACEUTICA SINICA, YAOXUE XUEBAO, CN, vol. 55, no. 6, 1 January 2020 (2020-01-01), CN , pages 1073 - 1080, XP093007357, ISSN: 0513-4870, DOI: 10.16438/j.0513-4870.2020-0319 *
NG SWEE LI, KHAW KOOI-YEONG, ONG YONG SZE, GOH HUI POH, KIFLI NUROLAINI, TEH SIEW PHOOI, MING LONG CHIAU, KOTRA VIJAY, GOH BEY HIN: "Licorice: A Potential Herb in Overcoming SARS-CoV-2 Infections", JOURNAL OF EVIDENCE-BASED COMPLEMENTARY & ALTERNATIVE MEDICINE, vol. 26, 1 January 2021 (2021-01-01), pages 2515690X2199666, XP093007354, ISSN: 2515-690X, DOI: 10.1177/2515690X21996662 *

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