WO2023149204A1 - Agent thérapeutique contre la covid-19, composition orale pour le traitement de la covid-19, et utilisation de composés pour la fabrication d'un agent thérapeutique contre la covid-19 - Google Patents

Agent thérapeutique contre la covid-19, composition orale pour le traitement de la covid-19, et utilisation de composés pour la fabrication d'un agent thérapeutique contre la covid-19 Download PDF

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Publication number
WO2023149204A1
WO2023149204A1 PCT/JP2023/001263 JP2023001263W WO2023149204A1 WO 2023149204 A1 WO2023149204 A1 WO 2023149204A1 JP 2023001263 W JP2023001263 W JP 2023001263W WO 2023149204 A1 WO2023149204 A1 WO 2023149204A1
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covid
protopanaxadiol
therapeutic
sc2r
sars
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Japanese (ja)
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正徳 池田
緑 武田
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Kagoshima University NUC
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Kagoshima University NUC
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to COVID-19 therapeutic agents, oral compositions for COVID-19 therapeutic agents, and uses of compounds for the manufacture of COVID-19 therapeutic agents.
  • Non-Patent Document 1 quantitative evaluation of the amount of phosphorylation and protein due to SARS-CoV-2 infection in order to elucidate the mechanism of viral pathogenicity, and profiles such as changes in phosphorylation that disrupt kinases and pathways Based on this, promising compounds for the treatment of COVID-19 are being investigated.
  • the present invention has been made in view of the above circumstances, and has a high degree of safety.
  • the object is to provide the use of the compounds for the manufacture of
  • the COVID-19 therapeutic agent according to the first aspect of the present invention is Protopanaxadiol or a pharmacologically acceptable salt thereof is included.
  • the protopanaxadiol is is (20R)-protopanaxadiol; You can do it.
  • the oral composition for treating COVID-19 comprises Protopanaxadiol or a pharmacologically acceptable salt thereof is included.
  • the use according to the third aspect of the invention is Use of protopanaxadiol or a pharmacologically acceptable salt thereof for the manufacture of a COVID-19 therapeutic agent.
  • COVID-19 therapeutic drug and COVID-19 therapeutic oral composition according to the present invention are highly safe and can be applied clinically at an early stage.
  • FIG. 1 shows the organization of the genome of SARS-CoV-2.
  • B is a diagram showing the structure of the replicon DNA according to the example.
  • C shows fragments F1 to F10 obtained by dividing the replicon DNA shown in (B) into a plurality of fragments.
  • FIG. 4 is a diagram showing the effect of each compound contained in a compound library on the replication level of replicon RNA and cell viability.
  • FIG. 10 shows the response of the replication level of replicon RNA to the concentration of (20R)-protopanaxadiol. (20R)-Protopanaxadiol cell viability.
  • Figure 2 shows the antiviral activity of (20R)-protopanaxadiol and (20S)-protopanaxadiol.
  • COVID-19 therapeutic agents include protopanaxadiol and pharmacologically acceptable salts thereof.
  • Protopanaxadiol is abundantly contained in the roots of ginseng, a perennial herbaceous plant (Araliaceae) native to Northeast China and the Korean Peninsula, more specifically Panax ginseng CA Meyer.
  • Panax ginseng is also known as Panax ginseng (Korean ginseng) or Asian ginseng (Korean ginseng).
  • the root of Panax ginseng has long been used for medicinal or food purposes, particularly as a crude drug.
  • the protopanaxadiol is (20R)-protopanaxadiol, but it may be its optical isomer (20S)-protopanaxadiol.
  • COVID-19 therapeutics may include (20R)-protopanaxadiol and (20S)-protopanaxadiol.
  • the structures of (20R)-protopanaxadiol and (20S)-protopanaxadiol are shown in Formulas 1 and 2, respectively.
  • Protopanaxadiol may be synthesized by a known method, or may be obtained from Araliaceae ginseng such as Panax ginseng.
  • ginseng of the family Araliaceae When protopanaxadiol is obtained from ginseng of the family Araliaceae, protopanaxadiol may be obtained, for example, by extracting from ginseng of the family Araliaceae, may be obtained by enzymatic fermentation of ginseng of the family Araliaceae, or may be obtained by It may be obtained by hydrolyzing carrots.
  • Araliaceae ginseng When protopanaxadiol is obtained from Araliaceae ginseng, Araliaceae ginseng may be used as it is as it is collected from nature. and rhizome parts, or powder obtained by pulverizing roots and rhizome parts.
  • a method of extraction with a water-ethanol solution there are no particular restrictions on the method of obtaining by extraction, and a method of extraction with a water-ethanol solution, a supercritical extraction method, an HPLC extraction method, etc. may be selected as appropriate.
  • the mixing ratio of the water-ethanol solution is not particularly limited.
  • water: ethanol (V/V) is preferably 9:1 to 2:1, 3:1. more preferred.
  • the COVID-19 therapeutic drug according to the present embodiment may contain protopanaxadiol as an extract of Araliaceae ginseng, particularly Panax ginseng.
  • the COVID-19 therapeutic drug according to this embodiment may contain a salt of protopanaxadiol as an active ingredient as long as it exhibits antiviral activity against SARS-CoV-2.
  • Salts are not particularly limited, and examples include alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, hydrochlorides, hydrobromides, sulfates, and nitrates.
  • inorganic acid salts such as oxalates and phosphates, as well as acetates, propionates, hexanoates, cyclopentanepropionates, glycolates, pyruvates, lactates, malonates, succinates , malate, fumarate, tartrate, citrate, benzoate, o-(4-hydroxybenzoyl)benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-chlorobenzenesulfonate, 2-naphthalenesulfonate, p-toluenesulfonate, camphorsulfonate, 4- Methylbicyclo[2.2.2]oct-2-ene-1-carboxylate, glucoheptanoate, 3-
  • the COVID-19 therapeutic drug according to the present embodiment is manufactured by a known method, and contains % by mass, 0.001 to 99.6% by mass, 0.01 to 99.5% by mass, 0.1 to 99% by mass, 0.5 to 60% by mass, 1 to 50% by mass, or 1 to 20% by mass of protopanaxadiol or a salt thereof.
  • a COVID-19 therapeutic agent may be a solid or liquid formulation.
  • the COVID-19 therapeutic agent may contain any pharmacologically acceptable ingredient in addition to protopanaxadiol or its salt.
  • Optional ingredients include, for example, carriers, excipients, lubricants, binders, disintegrants, solvents, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. Additives such as preservatives, antioxidants, coloring agents and sweetening agents may also be incorporated into the COVID-19 therapeutic if desired.
  • the dosage of the COVID-19 therapeutic drug according to this embodiment is appropriately determined according to the sex, age, weight, symptoms, etc. of the subject.
  • the COVID-19 therapeutic agent is administered in an effective amount of protopanaxadiol or a salt thereof.
  • the effective amount is the amount of protopanaxadiol or a salt thereof necessary to obtain the desired result, suppressing the growth of SARS-CoV-2, or delaying the progression of symptoms due to SARS-CoV-2 infection. , the amount necessary to effect inhibition, prevention, reversal or cure.
  • the dosage of the COVID-19 therapeutic agent is, for example, 0.01 mg/kg to 1000 mg/kg, preferably 0.1 mg/kg to 200 mg/kg, more preferably 0.2 mg/kg to 20 mg/kg; It can be administered in one or more divided doses per day.
  • the COVID-19 therapeutic agent is administered 1 to 4 times per day.
  • the COVID-19 therapeutic may be administered at different dosing frequencies, such as daily, every other day, once a week, every other week and once a month. Amounts outside the above ranges can also be used, if desired.
  • COVID-19 therapeutics may be administered, for example, parenterally or orally.
  • parenteral administration intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, enteral administration, transmucosal administration, and the like may be used.
  • COVID-19 therapeutics may be administered via an infusion.
  • COVID-19 therapeutic agent can be formulated in any form.
  • COVID-19 therapeutic agents include tablets such as dragees, buccal tablets, coated tablets and chewable tablets, lozenges, pills, powders and capsules including soft capsules, granules, suspensions, emulsions and dry syrups. It may be a syrup containing and a liquid such as an elixir.
  • COVID-19 therapeutic agents may be injections, inhalants, transdermal absorption tapes, aerosols, suppositories, and the like.
  • the COVID-19 therapeutic drug will be administered to any subject as long as the subject is infected with SARS-CoV-2.
  • the COVID-19 therapeutic agent is preferably administered to vertebrates, more preferably mammals. Mammals include, for example, humans, chimpanzees and other primates, pigs and horses, as well as birds such as ducks and chickens.
  • a particularly preferred administration subject is a human.
  • the COVID-19 therapeutic agent according to the present embodiment is administered to subjects in whom SARS-CoV-2 is detected for the purpose of preventing the onset of symptoms during the period without clear symptoms or the incubation period after infection.
  • Protopanaxadiol contained in the COVID-19 therapeutic drug according to this embodiment has been confirmed to be safe in humans. Indeed, as shown in the examples below, the CC50 (50% cytotoxic concentration) of protopanaxadiol was well above the EC50 (50% effective concentration). Therefore, the COVID-19 therapeutic agent according to this embodiment has high antiviral activity and high safety.
  • Also provided in another embodiment is the use of protopanaxadiol or a salt thereof for the manufacture of a COVID-19 therapeutic agent.
  • methods of treating, ameliorating or preventing COVID-19 are provided. The method includes administering protopanaxadiol or a salt thereof to the subject. Also provided in another embodiment is protopanaxadiol or a salt thereof for use in treating COVID-19.
  • an anti-SARS-CoV-2 agent according to another embodiment comprises protopanaxadiol or a salt thereof.
  • the treatment of COVID-19 in this embodiment also includes improvement and prevention of COVID-19.
  • the COVID-19 therapeutic agent in this embodiment may be used as a COVID-19 prophylactic agent.
  • an oral composition for treating COVID-19 comprising protopanaxadiol or a pharmacologically acceptable salt thereof is provided.
  • Specific examples of the oral composition include supplements, food compositions, food and drink, functional foods, and food additives.
  • the form of the supplement is not particularly limited, and may be in any form such as tablets, powders, granules, capsules, sugar-coated tablets, films, troches, chewables, solutions, emulsions and suspensions.
  • a supplement may contain any ingredient normally used as a supplement.
  • “Functional food” means food or beverage that is ingested for the purpose of maintaining health.
  • the functional food food with specified health uses or food with nutrient function claims, which are foods with health claims, are preferable.
  • various additives used in food specifically, coloring agents, preservatives, thickening stabilizers, antioxidants, bleaching agents, antibacterial antifungal agents , acidulants, sweeteners, flavor enhancers, emulsifiers, enhancers, manufacturing agents, flavoring agents and the like may be added to the oral compositions.
  • Functional foods may be foods or beverages, and are not particularly limited as long as they can be taken orally.
  • functional foods include beverages, confectionery, processed grain products, paste products, dairy products, and seasonings.
  • beverages include nutritional drinks, soft drinks, black tea, green tea, and the like.
  • confectionery include candy, cookies, tablet confectionery, chewing gum and jelly.
  • Bread, rice, biscuits and the like are exemplified as processed grain noodles. Sausages, hams, fish cakes, and the like are examples of paste products.
  • Dairy products include butter and yogurt.
  • the oral composition may be added to food as a food additive.
  • the food additives may be pastes, gels, powders, liquids, suspensions, emulsions, granules, etc. so as to be easily added to foods.
  • the oral composition may contain water, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, functional ingredients, food additives, etc., to the extent that the anti-SARS-CoV-2 action is maintained. good.
  • the oral composition can be produced by a known method, optionally adding other ingredients than protopanaxadiol or a salt thereof.
  • the oral composition may be divided and stored in one or more containers so that the daily intake is the above-mentioned intake, in which case it is preferable that one container contains a daily dose of The oral composition is contained.
  • the oral composition contains protopanaxadiol or a salt thereof, and is provided in a manner distinguishable from other products as a product in that it is used for COVID-19.
  • at least one of the product packaging, instructions, and promotional material for the oral composition is labeled as having anti-SARS-CoV-2 activity.
  • BsaI (-) vector The restriction enzyme BsaI site (ggtctc) in the ampicillin resistant gene of pUC19 was transfected into "gAtctc" using QuickChange mutagenesis (manufactured by Stratagene) to construct a BsaI-deficient plasmid pUC19b.
  • FIG. 1(A) shows the organization of the genome of SARS-CoV-2.
  • the genome of SARS-CoV-2 consists of nonstructural regions including nonstructural protein gene 1a (ORF1a) and nonstructural protein gene 1b (ORF1b), S gene, ORF3a, E gene, M gene, ORF6, ORF7a, ORF7b, and a structural region containing ORF8, the N gene and ORF10.
  • ORF1a nonstructural protein gene 1a
  • ORF1b nonstructural protein gene 1b
  • the replicon DNA (hereinafter referred to as "SC2R") according to this example is a DNA construct constructed based on the nucleotide sequence of the genome of SARS-CoV-2.
  • the nucleotide sequence of SC2R is shown in SEQ ID NO:2.
  • a viral replicon maintains a nonstructural region and lacks a structural region, so that it does not have infectivity but propagates autonomously.
  • the structure of SC2R is shown in FIG. 1(B).
  • SC2R has the non-structural region of SARS-CoV-2 and has no genes contained in the structural region except the N gene.
  • SC2R consists of cytomegalovirus (CMV) promoter, ORF1a, ORF1b, secretory luciferase gene (sNLuc), N gene, poly A region (pA), hepatitis delta virus ribozyme gene (Rz ) and bovine growth hormone poly A signal (BGH).
  • CMV cytomegalovirus
  • ORF1a ORF1a
  • ORF1b secretory luciferase gene
  • N gene N gene
  • pA poly A region
  • Rz hepatitis delta virus ribozyme gene
  • BGH bovine growth hormone poly A signal
  • the N gene has the function of improving the replication level of genomic RNA.
  • SC2R is transcribed into RNA (replicon RNA) in cells, translated, and replicated. Duplicated SC2R can be quantified through the activity of sNLuc.
  • Neo is a drug resistance gene as a marker gene.
  • pA contributes to transcript stability.
  • Rz is required for excision by self-cleavage after replication. BGH terminates transcription.
  • SC2R was synthesized by artificial synthesis without using a natural virus as a template, by the golden gate method using type IIS restriction enzyme, as follows.
  • Ggacc was used to synonymously replace the base sequence corresponding to the BsaI site (gagacc) from 17972nd to 17977th from the 5' end of the base sequence shown in SEQ ID NO: 1.
  • a BsaI site was introduced at the 5' and 3' ends of each of the 10 fragments.
  • F1-4 and F6-10 were introduced into pUC19b (pUC19b/SC2R-F1, F2, F3, F4, F6, F7, F8, F9, F10).
  • F5 was introduced into the pCC1-4k vector (pCC1-4k/SC2R-F5).
  • PCR fragments A and B containing BsaI inside EcoRI and BamHI were prepared.
  • PCR fragment A was performed using the HRP gene shown in SEQ ID NO: 4 as a template and a forward primer (SEQ ID NO: 5) and a reverse primer (SEQ ID NO: 6).
  • the nucleotide sequence of PCR fragment A is shown in SEQ ID NO:7.
  • PCR was performed using the HRP gene shown in SEQ ID NO: 4 as a template and a forward primer (SEQ ID NO: 8) and a reverse primer (SEQ ID NO: 9).
  • the nucleotide sequence of PCR fragment B is shown in SEQ ID NO:10.
  • PCR fragment C containing BsaI inside HindIII and BamHI was prepared.
  • PCR was performed using the HRP gene shown in SEQ ID NO: 4 as a template and a forward primer (SEQ ID NO: 11) and a reverse primer (SEQ ID NO: 12).
  • the nucleotide sequence of PCR fragment C is shown in SEQ ID NO:13.
  • pHSG298 was cleaved with EcoRI and BamHI, and PCR fragment A was ligated to construct pHSG298c vector A. Further, pHSG298 was cleaved with EcoRI and BamHI, and PCR fragment B was ligated to construct pHSG298c vector B. pCC1-4k was cleaved with HindIII and BamHI and PCR fragment C was ligated to construct pCC1-4kc vector.
  • PCR was performed using pSMART BACbc/SC2R as a template to amplify the N gene of SARS-CoV-2.
  • the nucleotide sequences of the forward primer and reverse primer used for the PCR are shown in SEQ ID NOs: 14 and 15, respectively.
  • a PCR fragment was prepared by introducing MluI and NotI sites at the 5' end and 3' end, and the PCR fragment was ligated to the pCX4bsr vector cleaved with MluI and NotI to construct the pCX4bsr/SARS-CoV-2-N vector. .
  • the cured cell line has a higher level of HCV RNA replication than the parent HuH-7 cell line (Masanori Ikeda, et al., ⁇ Efficient replication of a full-length hepatitis C virus genome, strain O,''). in cell culture, and development of a luciferase reporter system,” Biochem Biophys Res Commun., 2005, 329(4):1350-9).
  • HuH-7.6c cells were seeded in a 6-well plate at 1 ⁇ 10 5 cells/well, and the next day, 2 ⁇ g of pSMART BACbc/SC2R was transfected using Fugene HD reagent and introduced into the cells. After 24 hours, cells were detached using trypsin and seeded at 3 x 104 cells/well in 24-well plates. After an additional 24 hours, compounds were added to the indicated concentrations. After culturing for 48 hours, the culture supernatant was collected and luciferase activity was measured using the Nano-Glo Luciferase Assay System.
  • HuH-7.6c cells were seeded in 96-well plates at 5 ⁇ 10 3 cells. Twenty-four hours after the initiation of culture, compounds were added to the cells at the given concentrations. After culturing for 48 hours, 10 ⁇ l of Premix WST-1 Cell Proliferation Assay System (manufactured by Takara Bio Inc.) was added to the medium, cultured at 37° C. for 2 hours, and absorbance at 450 nm was measured using a microplate reader.
  • Premix WST-1 Cell Proliferation Assay System manufactured by Takara Bio Inc.
  • FIG. 3 shows the SC2R assay results for (20R)-protopanaxadiol and (20S)-protopanaxadiol.
  • (20R)-protopanaxadiol inhibited luciferase activity in a concentration-dependent manner with an EC50 of 5.46 ⁇ M.
  • (20S)-protopanaxadiol was also found to inhibit luciferase activity.
  • FIG. 4 shows cell viability at each concentration of (20R)-protopanaxadiol.
  • the CC 50 of (20R)-protopanaxadiol was 26.7 ⁇ M.
  • Fig. 5 shows the results of Western blot analysis and the relative values of luciferase activity. It was confirmed that (20R)-protopanaxadiol and (20S)-protopanaxadiol suppress the expression of N protein.
  • the present invention is useful for treating COVID-19.

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Abstract

Le présent agent thérapeutique contre la COVID-19 contient du protopanaxadiol ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2023/001263 2022-02-03 2023-01-18 Agent thérapeutique contre la covid-19, composition orale pour le traitement de la covid-19, et utilisation de composés pour la fabrication d'un agent thérapeutique contre la covid-19 Ceased WO2023149204A1 (fr)

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Publication number Priority date Publication date Assignee Title
ES3030208A1 (es) * 2023-12-26 2025-06-26 Creaciones Aromaticas Ind S A Producto alimentario antiviral
WO2025141238A1 (fr) * 2023-12-26 2025-07-03 Creaciones Aromáticas Industriales, S.A. Produit alimentaire antiviral

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