WO2023241179A1 - Utilisation d'acide asiatique dans la préparation d'un médicament pour le traitement de l'hépatite b - Google Patents

Utilisation d'acide asiatique dans la préparation d'un médicament pour le traitement de l'hépatite b Download PDF

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WO2023241179A1
WO2023241179A1 PCT/CN2023/086552 CN2023086552W WO2023241179A1 WO 2023241179 A1 WO2023241179 A1 WO 2023241179A1 CN 2023086552 W CN2023086552 W CN 2023086552W WO 2023241179 A1 WO2023241179 A1 WO 2023241179A1
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hepatitis
asiatic acid
hbv
levels
preparation
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PCT/CN2023/086552
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English (en)
Chinese (zh)
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陈娟
杨祯
程胜桃
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重庆医科大学检验医学院
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to the field of biomedicine technology, and in particular to the use of asiatic acid in the preparation of hepatitis B therapeutic drugs.
  • Hepatitis B virus (HBV) infection is a major public health problem worldwide. According to WHO, approximately 2 billion people worldwide have been infected with HBV, including approximately 257 million patients with chronic hepatitis B infection. my country is an area with high prevalence of HBV. There are about 97 million hepatitis B virus carriers, accounting for 8% to 10% of the country's total population, of which about 20 million are chronic hepatitis B patients. Every year, there are as many as 263,000 deaths due to complications such as cirrhosis and liver cancer caused by chronic hepatitis B. . Therefore, the task of preventing and controlling hepatitis B is very serious.
  • interferon interferon
  • NAs nucleoside analogs
  • both types of drugs have certain shortcomings, such as nucleoside analogues, which take a long time to take, poor patient compliance, and are prone to rebound after drug withdrawal.
  • Interferons are only effective in less than 30% of patients and have many adverse reactions. More importantly, neither type of drugs can effectively cure hepatitis B, so there is an urgent need to develop new anti-HBV drugs.
  • HBV belongs to the hepadnaviridae family, and its genome is a partially double-stranded, relaxed circular DNA (relaxed-circular DNA, rcDNA) of approximately 3.2 kb in length.
  • rcDNA relaxed circular DNA
  • rcDNA is delivered to the nucleus and forms covalently closed circular DNA (cccDNA) with a superhelical structure.
  • cccDNA persists in the nucleus of liver cells in the form of minichromosomes, has a stable structure, and serves as a transcription template for viral RNA. Therefore, cccDNA is the main cause of persistent HBV infection, drug resistance, and HBV reactivation after discontinuation of antiviral drugs.
  • the virus can encode a transactivator protein - HBx, which can hijack DDB1 to relieve the ubiquitination and degradation of Smc5/6 by the E3 ubiquitin ligase CUL4B and activate cccDNA transcription. It can also activate cccDNA transcription through Binding to the cccDNA minichromosome inhibits the recruitment of transcriptional repressors to cccDNA thereby maintaining cccDNA transcription.
  • HBx plays a key role in the transcription process of cccDNA. Inhibiting the function of HBx may inhibit cccDNA transcription. Therefore, HBx is an important target for new therapies to treat chronic HBV infection.
  • the development of new drugs that target and inhibit HBx can provide new directions and theoretical basis for reducing the infection rate of HBV and exploring new drugs for the effective treatment of hepatitis B. .
  • the purpose of the present invention is to provide the use of asiatic acid in the preparation of hepatitis B therapeutic drugs.
  • Asiatic acid can target HBx and provide a new drug for the effective treatment of hepatitis B. and technical means.
  • the first aspect of the present invention provides the use of asiatic acid as an active ingredient in the preparation of hepatitis B therapeutic drugs.
  • hepatitis B treatment drug has at least one of the following functions:
  • Reduce HBsAg levels reduce intracellular total HBV RNAs levels, reduce intracellular HBV 3.5-kb RNA levels, and reduce HBV DNA levels.
  • the hepatitis B treatment drug must include asiatic acid, and use asiatic acid as the aforementioned function. of active ingredients.
  • the active ingredient that performs the aforementioned functions may only be asiatic acid, or may include other molecules that can perform similar functions.
  • the asiatic acid is used as one of the active ingredients or the only active ingredient of the hepatitis B treatment drug.
  • the hepatitis B treatment drug may be a single-component substance or a multi-component substance.
  • the form of the hepatitis B treatment drug is not particularly limited and can be in various material forms such as solid, liquid, gel, semi-liquid, aerosol, etc.
  • hepatitis B therapeutic drugs are mainly targeted at mammals, such as rodents, primates, etc.
  • the second aspect of the present invention provides a pharmaceutical preparation for treating hepatitis B, including a safe and effective dose of asiatic acid.
  • the pharmaceutical preparation for treating hepatitis B includes 10-30 ⁇ M asiatic acid.
  • the dosage of the pharmaceutical preparation for treating hepatitis B is 15-30 mg/kg asiatic acid.
  • the pharmaceutical preparation for treating hepatitis B also includes pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical preparation for treating hepatitis B must include asiatic acid, and use asiatic acid as an active ingredient for the aforementioned functions.
  • the active ingredient that performs the aforementioned functions may only be asiatic acid, or may include other molecules that can perform similar functions.
  • the asiatic acid is used as one of the active ingredients or the only active ingredient of the pharmaceutical preparation for treating hepatitis B.
  • the pharmaceutical preparation for treating hepatitis B may be a single-component substance or a multi-component substance.
  • the form of the pharmaceutical preparation for treating hepatitis B is not particularly limited and can be in various material forms such as solid, liquid, gel, semi-liquid, aerosol, etc.
  • the pharmaceutical preparations for treating hepatitis B are mainly targeted at mammals, such as rodents, primates, etc.
  • a third aspect of the present invention provides a method for treating hepatitis B, which includes administering asiatic acid to a subject.
  • the subject may be a mammal or a mammalian hepatitis B cell.
  • the mammal is preferably a rodent, an artiodactyl, a perissodactyl, a lagomorph, a primate, etc.
  • the primate is preferably a monkey, ape or human.
  • the hepatitis B cells may be isolated hepatitis B cells.
  • the subject may be a patient suffering from hepatitis B or an individual with hepatitis B who is looking forward to treatment.
  • the subject is hepatitis B cells from a hepatitis B patient or an individual who is expected to treat hepatitis B.
  • the asiatic acid can be administered to the subject before, during and after hepatitis B treatment.
  • the fourth aspect of the present invention provides a hepatitis B combined treatment drug combination, including a safe and effective dose of asiatic acid and at least one other hepatitis B treatment drug, with the balance being pharmaceutically acceptable carriers and/or excipients.
  • hepatitis B combined treatment drug combination can be in any of the following forms:
  • Asiatic acid and other hepatitis B therapeutic drugs are made into independent preparations.
  • the dosage forms of the preparations can be the same or different, and the routes of administration can also be the same or different.
  • hepatitis B therapeutic drugs are antibodies
  • parenteral administration is generally used.
  • the administration form can be relatively rich, and it can be gastrointestinal administration or parenteral administration. It is generally recommended that each chemical drug be administered by a known route of administration.
  • hepatitis B therapeutic drugs are drugs that are known before the filing date of this application and can be used to treat hepatitis B, such as antiviral drugs: interferon (IFN), nucleoside analogs, etc.
  • IFN interferon
  • nucleoside analogs etc.
  • a fifth aspect of the present invention provides a method for treating hepatitis B, which includes administering an effective amount of asiatic acid to a subject and administering an effective amount of other hepatitis B therapeutic drugs to the subject and/or implementing other hepatitis B treatment methods to the subject. .
  • an effective dose of asiatic acid and at least one effective dose of other hepatitis B therapeutic drugs can be administered simultaneously or sequentially.
  • Asiatic acid is the first hepatitis B therapeutic drug discovered by the present invention. When used in combination with other hepatitis B therapeutic drugs other than asiatic acid, it can at least have an additive effect and further enhance the efficacy of hepatitis B. Therapeutic effect.
  • hepatitis B treatment drugs include but are not limited to: antibody drugs, chemical drugs or targeted drugs, etc.
  • the asiatic acid can be administered through the gastrointestinal tract or parenterally, and the other hepatitis B therapeutic drugs can be administered through the gastrointestinal tract or parenterally.
  • parenteral administration is generally used.
  • the sixth aspect of the present invention provides the use of asiatic acid in preparing substances with any one or more of the following effects: use in preparing substances that inhibit HBx protein; use in preparing substances that inhibit HBsAg levels; Use in the preparation of substances that inhibit the level of total HBV RNAs in cells; use in the preparation of substances that inhibit the level of HBV 3.5-kb RNA in cells; use in the preparation of substances that inhibit the level of HBV DNA.
  • asiatic acid of the present invention in the preparation of hepatitis B therapeutic drugs has the following beneficial effects:
  • the present invention found for the first time that asiatic acid can reduce HBx protein levels, inhibit cccDNA transcription activity and thereby reduce intracellular total HBV RNAs, HBV 3.5-kb RNA levels and HBsAg levels in the supernatant, and can effectively reduce serum levels in the recombinant cccDNA mouse model.
  • HBsAg, HBV DNA levels, and liver tissue HBV RNA and HBV DNA levels are potential new drugs targeting HBx.
  • the present invention provides a new direction and theoretical basis for reducing the infection rate of HBV and exploring new drugs for effective treatment of hepatitis B, and has great application prospects in the treatment of hepatitis B.
  • Figure 1 shows the MTT assay analyzing the cytotoxicity of asiatic acid in HepG2-NTCP and HepG2.2.15 cells.
  • Figure 2 shows the Western blot detection of the effect of asiatic acid on the protein levels of 3 ⁇ Flag-HBx and 2 ⁇ HA-HBx.
  • Figure 3 shows the fluorescence quantitative PCR method and Northern blot experiment to detect the effect of asiatic acid on total HBV RNAs and HBV3.5-kb RNA.
  • Figure 4 shows the fluorescence quantitative PCR method and Southern blot experiment to detect the effect of asiatic acid on HBV DNA.
  • Figure 5 shows the ELISA test of the effect of asiatic acid on HBsAg secretion.
  • Figure 6 shows the Taq Man probe PCR experiment to detect the effect of asiatic acid on cccDNA levels and transcriptional activity.
  • Figure 7 shows the fluorescence quantitative PCR method and Northern blot experiment to detect the effect of asiatic acid on total HBV RNAs and HBV 3.5-kb RNA in HepG2.2.15 cells.
  • Figure 8 shows the fluorescence quantitative PCR method and Southern blot experiment to detect the effect of asiatic acid on HBV DNA in HepG2.2.15 cells.
  • Figure 9 shows the Taq Man probe PCR experiment to detect the effect of asiatic acid on cccDNA in HepG2.2.15 cells.
  • Figure 10 shows a mouse handling flow chart.
  • Figure 11 shows the effects of asiatic acid on HBsAg and HBV DNA levels in mouse serum detected by ELISA and fluorescence quantitative PCR.
  • Figure 12 shows the fluorescence quantitative PCR method to detect the effect of asiatic acid on HBV RNA levels in mouse liver tissue.
  • Figure 13 shows the fluorescence quantitative PCR method to detect the effect of asiatic acid on HBV DNA levels in mouse liver tissue.
  • Asiatic acid often referred to as AA, the Chinese name is Asiatic acid. It has shown antihypertensive, neuroprotective, cardioprotective, antibacterial and antitumor activities in preclinical studies.
  • the present invention's research found that AA can reduce HBx protein levels, inhibit cccDNA transcription activity and thereby reduce intracellular total HBV RNAs, HBV 3.5-kb RNA levels and HBsAg levels in the supernatant, and can effectively reduce HBsAg in serum in the recombinant cccDNA mouse model.
  • HBV DNA levels, and liver tissue HBV RNA and HBV DNA levels which are potential new drugs targeting HBx.
  • the present invention provides the use of asiatic acid as an active ingredient in the preparation of hepatitis B therapeutic drugs.
  • the hepatitis B treatment drug also includes one or more pharmaceutically acceptable carriers or excipients according to the needs of different pharmaceutical dosage forms.
  • “Pharmaceutically acceptable” means that the molecular entities and compositions do not produce adverse, allergic or other adverse reactions when properly administered to animals or humans.
  • the pharmaceutical dosage form is not particularly limited and can be made into dosage forms such as injections, oral liquids, tablets, capsules, dropping pills, sprays, etc., and can be prepared by conventional methods.
  • the choice of drug dosage form should match the mode of administration.
  • the present invention also provides a drug combination and administration method for combined treatment of hepatitis B.
  • the hepatitis B combined treatment drug combination can be in any of the following forms:
  • Asiatic acid and other hepatitis B therapeutic drugs are made into independent preparations.
  • the dosage forms of the preparations can be the same or different, and the routes of administration can also be the same or different.
  • several medicines can be used at the same time, or several medicines can be used one after another.
  • administering drugs sequentially other drugs should be administered to the body while the first drug is still effective.
  • hepatitis B therapeutic drugs are antibodies, they are generally administered parenterally, such as intravenous injection, intravenous drip, or arterial infusion. Its usage and dosage can refer to the existing technology.
  • hepatitis B treatment drugs are chemical drugs
  • the administration forms can be richer, and they can be gastrointestinal or parenteral. It is generally recommended that each chemical drug be administered by a known route of administration.
  • combination of drugs in the present invention refers to a reasonable combination of drugs, which should be based on the basic principle of improving efficacy and/or reducing adverse reactions.
  • drug interactions should include interactions that affect pharmacokinetics and pharmacodynamics.
  • types of drugs should be reduced as much as possible to reduce adverse drug reactions caused by drug interactions, avoid affecting drug efficacy or increasing toxicity, and avoid producing opposite results.
  • HepG2-NTCP cells were cultured in DMEM medium containing 10% fetal calf serum, 1% penicillin–streptomycin, and 2ug/mL doxycycline, and HepG2.2.15 cells were cultured in DMEM medium containing 10% fetal calf serum, 1% penicillin– Streptomycin and 400ug/mL G418 in DMEM culture medium, placed in a 37°C, 5% CO2 incubator.
  • Asiatic acid (cas no. 464-92-6) was purchased from MCE.
  • prcccDNA and pCMV-KRAB-Cre were gifts from Professor Deng Qiang (Fudan University, Shanghai, China).
  • 3 ⁇ Flag-HBx was constructed by inserting full-length HBx into p3 ⁇ Flag-CMV7.1.
  • 3 ⁇ Flag-HBx was constructed by inserting full-length HBx into p3 ⁇ Flag-CMV7.1.
  • 2 ⁇ HA HBx was a gift from Professor Jieliang Chen (Fudan University, Shanghai, China).
  • Asiatic acid (cas number 464-92-6) was purchased from MCE Company, dissolved in DMSO, prepared into a 20mM storage solution, aliquoted and stored Store at –80°C until use.
  • HepG2-NTCP cells and HepG2.2.15 cells were seeded in a 96-well culture plate at 15 ⁇ 10 4 /ml. After culturing for 24 hours, use DMEM medium to dilute asiatic acid to 8 concentration gradients of 200, 100, 50, 25, 12.5, 6.25, 3.125, and 0uM. Set up 3 replicate wells for each concentration, and set up a normal cell control. After 72 hours, add 10ul MTT reagent, incubate at 37°C for 4 hours, add 100ul DMSO, shake for 10 minutes, detect the OD value at 490nm with a microplate reader, calculate and draw the cell activity curve.
  • HepG2-NTCP cells were seeded in twelve-well plates at 20 ⁇ 10 4 /ml. After 24 hours of culture, 3 ⁇ Flag-HBx and 2 ⁇ HA-HBx were transfected respectively; 24 hours after transfection, asiatic acid was diluted to 4 concentration gradients of 30, 20, 10, and 0uM using DMEM medium, and HepG2- were treated respectively. NTCP cells. After 48 h, total protein was extracted and Western blot was used to detect HBx protein levels.
  • HepG2-NTCP cells were seeded in twelve-well plates at 20 ⁇ 10 4 /ml. After culturing for 24 hours, use DMEM medium to dilute asiatic acid to 4 concentration gradients of 30, 20, 10, and 0uM. HepG2-NTCP cells were treated for 3 days, 6 days, and 9 days respectively. The medium supernatant and cells were collected, and the supernatant was detected by ELISA.
  • HBsAg levels, Real-time PCR and Northern blot were used to detect total HBV RNAs and HBV 3.5-kb RNA levels in cells, and Real-time PCR and Southern blot were used to detect HBV DNA levels in cells.
  • HepG2.2.15 cells were seeded in twelve-well plates at 20 ⁇ 10 4 /ml. After culturing for 24 hours, HepG2.2.15 cells were treated with DMEM medium diluted with asiatic acid to 4 concentration gradients of 30, 20, 10, and 0uM. The cells were collected after 4 days. Real-time PCR and Northern blot were used to detect total HBV RNAs and total HBV RNAs in the cells. HBV 3.5-kb RNA level, Real-time PCR and Southern blot were used to detect HBV DNA level in cells.
  • mice Fifty male C57BL/6 mice, aged 6-8 weeks and weighing 18-20g, were selected. 4 ⁇ g of plasmid prcccDNA and 4 ⁇ g of plasmid pCMV-KRAB-Cre were injected into the tail vein respectively. One week later, the serum HBV DNA copy number was detected by fluorescence quantitative PCR to determine whether the model was successfully established.
  • mice The successfully modeled mice were randomly divided into four groups: negative control, positive control, low-concentration experimental group, and high-concentration experimental group.
  • Six mice in each group were orally administered 0.9% normal saline, 0.02mg/kg entecavir, and 15mg/kg entecavir.
  • the liver tissue was ground to detect the levels of HBV RNAs and HBV DNA.
  • HBV DNA primers F: CCTAGTAGTCAGTTATGTCAAC (SEQ ID NO.1), R: TCTATAAGCTGGAGGAGTGCGA (SEQ ID NO.2 ). Three duplicate wells were set up for each sample, and each set of experiments was repeated three times.
  • Detect HBV RNA cDNA synthesized by reverse transcription RNA, prepare the reaction system and set the reaction conditions according to the instructions of SYBR Green (Bio Rad).
  • the HBV 3.5kb RNA primers are F: CTCTTCCAGCCTTCCTTCCT (SEQ ID NO. 3), R: AGCACTGTGTTGGCGTACAG (SEQ ID NO.4), the total HBV RNAs primer is F:ACCGACCTTGAGGCATACTT (SEQ ID NO. 5), R: GCCTACAGCCTCCTAGTACA (SEQ ID NO. 6).
  • Three duplicate wells were set up for each sample, and each set of experiments was repeated three times.
  • Figure 1 shows the MTT assay analyzing the cytotoxicity of asiatic acid in HepG2-NTCP and HepG2.2.15 cells.
  • the results shown in Figure 1 show that asiatic acid has a CC50 of 74.82 ⁇ M in the HBV-infected cell line HepG2-NTCP and a CC50 of 67.6 ⁇ M in the HBV stable replication model HepG2.2.15.
  • Figure 2 shows the Western blot detection of the effect of asiatic acid on the protein levels of 3 ⁇ Flag-HBx and 2 ⁇ HA-HBx.
  • the Western blot results shown in Figure 2 show that after asiatic acid treatment, the protein levels of exogenous 3 ⁇ Flag-HBx and 2 ⁇ HA-HBx in HepG2-NTCP cells decreased in a concentration gradient-dependent manner, suggesting that asiatic acid can inhibit HBx Express.
  • Figure 3 shows the fluorescence quantitative PCR method and Northern blot experiment to detect the effect of asiatic acid on total HBV RNAs and HBV3.5-kb RNA.
  • the Real-time PCR results shown in Figure 3 show that compared with the negative control group, asiatic acid significantly reduced the levels of total HBV RNAs and HBV 3.5-kb RNA in a time- and concentration-gradient-dependent manner.
  • Northern blot verified the PCR results .
  • Figure 4 shows the fluorescence quantitative PCR method and Southern blot experiment to detect the effect of asiatic acid on HBV DNA levels.
  • the Real-time PCR results shown in Figure 4 show that compared with the negative control group, asiatic acid significantly reduced the level of intracellular HBV DNA in a time- and concentration-gradient-dependent manner. Southern blot verified the PCR results.
  • Figure 5 shows the ELISA test of the effect of asiatic acid on HBsAg secretion.
  • the ELISA results shown in Figure 5 show that asiatic acid can effectively reduce the level of HBsAg in HepG2-NTCP cells in a time- and concentration gradient-dependent manner.
  • Figure 6 shows the Taq Man probe PCR experiment to detect the effect of asiatic acid on cccDNA levels and transcriptional activity. Because HBx plays a key role in the transcription process of cccDNA. Inhibiting the function of HBx may inhibit cccDNA transcription. Therefore, the effect of asiatic acid on cccDNA transcription was further determined.
  • the Taq Man probe PCR experimental results shown in Figure 6 show that asiatic acid has no significant effect on cccDNA levels. Further analysis of cccDNA transcription activity (total RNAs/cccDNA and pgRNA/cccDNA ratio) found that asiatic acid can significantly inhibit cccDNA transcription activity.
  • Figure 7 shows the detection of the effect of asiatic acid on total HBV RNAs and HBV 3.5-kb RNA in HepG2.2.15 cells.
  • Figure 8 shows the detection of the effect of asiatic acid on HBV DNA in HepG2.2.15 cells. The results showed that asiatic acid could significantly inhibit intracellular HBV RNA ( Figure 7) and HBV DNA levels (Figure 8), but did not affect the cccDNA level ( Figure 9).
  • Figure 10 shows a mouse handling flow chart.
  • Figure 11 shows the effects of asiatic acid on HBsAg and HBV DNA levels in mouse serum detected by ELISA and fluorescence quantitative PCR.
  • Figure 12 shows the fluorescence quantitative PCR method to detect the effect of asiatic acid on HBV RNA levels in mouse liver tissue.
  • Figure 13 shows the fluorescence quantitative PCR method for detecting the effect of asiatic acid on HBV in mouse liver tissue. DNA level effects.

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Abstract

La présente invention porte sur l'utilisation de l'acide asiatique dans la préparation d'un médicament pour le traitement de l'hépatite B. L'acide asiatique peut réduire le niveau de la protéine HBx et inhiber l'activité de transcription de l'ADNccc de manière à réduire les niveaux d'ARN du VHB total et d'ARN 3,5 kb du VHB dans les cellules ainsi que les niveaux de HBsAg dans le surnageant, et peut réduire efficacement les niveaux de HBsAg et d'ADN du VHB dans le sérum ainsi que les niveaux d'ARN du VHB et d'ADN du VHB dans le tissu hépatique dans un modèle de souris à ADNcc recombinant. Il s'agit d'un nouveau médicament potentiel ciblant le HBx, et il peut être utilisé pour le traitement de l'hépatite B.
PCT/CN2023/086552 2022-06-17 2023-04-06 Utilisation d'acide asiatique dans la préparation d'un médicament pour le traitement de l'hépatite b WO2023241179A1 (fr)

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