New Use of Compound Pladienolide B in Anti-Abrin

Abstract

The present invention discloses a new use of the compound Pladienolide B in anti- Abrus precatorius toxin. For the first time, the present invention creatively discovers that Pladienolide B has an anti- Abrus precatorius toxin toxic effect and can be used in the development of anti- Abrus precatorius toxin drugs. The present invention provides a theoretical basis for the research and development of anti- Abrus precatorius toxin drugs, opens up a new use of Pladienolide B, provides a brand-new method for treating or preventing diseases or symptoms related to Abrus precatorius toxin poisoning, and has broad application prospects in the technical field of treating diseases or symptoms related to Abrus precatorius toxin poisoning.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically, relates to a new use of the compound Pladienolide B in anti - abrin toxin. Background Art

[0002] Abrin is a toxic protein present in the seeds of the leguminous plant Abrus precatorius. Its toxicity far exceeds that of ricin, and a trace amount can cause severe cell damage or even death. This toxin inhibits protein synthesis within cells, disrupts cell functions, and then causes multiple organ failure. Once a substance containing abrin is ingested, initial symptoms may include gastrointestinal reactions such as nausea, vomiting, and diarrhea. As the toxin spreads in the body, it quickly erodes important organs of the human body, causing irreversible damage to the liver, kidneys, heart, etc., and even leading to death in severe cases. Moreover, abrin is stable in nature, and conventional treatment methods are difficult to completely inactivate it, which undoubtedly further increases the difficulty of prevention and control. Due to the high toxicity of abrin and its potential bioterror threat, the research on abrin not only concerns the medical field but also involves public safety.

[0003] However, there is still a blank in the specific antidote drugs for abrin at present, which makes the research and development of new drugs against abrin toxin an urgent and important task. Given the great harm of abrin toxin, it is extremely urgent to develop new drugs against abrin toxin. Currently, for abrin toxin poisoning, there are no specific therapeutic drugs and mature treatment plans. Most of the existing treatment methods can only relieve symptoms and cannot fundamentally remove the toxin and save the patient's life. Developing new drugs against abrin toxin can not only fill the blank in this direction in the medical field, provide effective treatment means for patients with abrin toxin poisoning, and significantly improve the survival rate of patients, but also be of great significance for maintaining public health safety. Pladienolide B is the main analogue of the macrolide family isolated from Streptomyces. In the field of anti - abrin toxin, the research on Pladienolide B is still blank. Summary of the Invention

[0004] The purpose of the present invention is to provide a new use of the compound Pladienolide B in anti - abrin toxin, and to provide a safe and effective drug for the treatment of diseases or symptoms related to abrin toxin poisoning, so as to overcome the technical problem that there is an urgent need for effective anti - abrin toxin drugs in the current field.

[0005] The above - mentioned invention purpose of the present invention is achieved through the following technical solutions:

[0006] In a first aspect, the present invention provides the use of Pladienolide B or a pharmaceutically acceptable salt thereof in the preparation of a drug against abrin toxin, and the structural formula of the Pladienolide B is shown in Formula (I):

[0007]

[0008] Formula (I).

[0009] Furthermore, the Pladienolide B has an anti-abrin toxin toxic effect.

[0010] Furthermore, the drug further comprises a pharmaceutically acceptable excipient and / or vehicle.

[0011] Furthermore, the dosage form of the drug is an oral dosage form, a parenteral dosage form or a topical dosage form.

[0012] Furthermore, the dosage form of the drug is a solution, a powder for injection, a tablet, a capsule, a granule, a powder, a pill, an aerosol or a suspension.

[0013] Furthermore, the administration dosage of the Pladienolide B or a pharmaceutically acceptable salt thereof is 10 nM - 100 mM.

[0014] Furthermore, the administration dosage of the Pladienolide B or a pharmaceutically acceptable salt thereof is 50 nM - 100 nM.

[0015] In the present invention, the Pladienolide B is the main analogue of the macrolide family isolated from Streptomyces, and its corresponding Chinese name is pradimicin B. Pladienolide B is a highly efficient inhibitor of hypoxia signaling and cancer cell proliferation. Currently, there is no research or report on the anti-abrin toxin toxic effect of Pladienolide B. Its corresponding CAS number is 445493-23-2, the molecular formula is C 30 H 48 O8, the molecular weight is 536.70, and the structural formula is shown in the above Formula (I). The present invention has no particular limitation on the specific source of the Pladienolide B, and those skilled in the art can obtain it through conventional channels.

[0016] In some embodiments, the hydrate, enantiomer, diastereomer, solvate, crystalline form or derivative corresponding to the Pladienolide B is also within the protection scope of the present invention, that is, the use of the hydrate, enantiomer, diastereomer, solvate, crystalline form or derivative corresponding to the Pladienolide B in the preparation of a drug against abrin toxin also falls within the protection scope of the present invention.

[0017] In some embodiments, the pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt of Pladienolide B. Specifically, the pharmaceutically acceptable salt of Pladienolide B refers to a salt form obtained by salifying Pladienolide B and suitable for use in pharmaceutical formulations and clinical applications. The salts used in the salifying process include, but are not limited to: inorganic acid salts (e.g., hydrochloride, sulfate, phosphate), organic acid salts (e.g., citrate, maleate, tartrate), and these salts are suitable for contact with patients within the scope of sound medical judgment and will not produce undue toxicity, irritation, allergic reactions, etc.

[0018] In some embodiments, examples of the pharmaceutically acceptable salts of Pladienolide B include, but are not limited to: salts having (as counterions) alkali metal ions such as Na + , Li + or K + , or salts having alkaline earth metal ions such as Ca 2+ or Mg 2+ , or salts having any other pharmaceutically acceptable metal ions such as Zn 2+ or Al 3+ ; or pharmaceutically acceptable salts formed with organic bases such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine or tromethamine.

[0019] In some embodiments, the pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are magnesium, potassium, sodium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, diethanolamine, chloroprocaine, choline, ethylenediamine, N-methylglucamine or procaine.

[0020] In some embodiments, the base addition salts of acidic compounds can be prepared by the following method: contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and then separating the free acid.

[0021] In some embodiments, the pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals, such as sodium, potassium, calcium, lithium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to: ammonium, tetramethylammonium, methylamine, dimethylamine, tetraethylammonium, trimethylamine, triethylamine, ethylamine, etc. Also covered are salts of amino acids, such as gluconate, arginine salt, galacturonate, etc.

[0022] In a specific embodiment of the present invention, the present invention proves through cell experiments that Pladienolide B has an anti- Abrus precatorius toxin toxicity effect, that is, it proves the effectiveness of Pladienolide B against Abrus precatorius toxin, and Pladienolide B or its pharmaceutically acceptable salt can be effectively used in the preparation of anti- Abrus precatorius toxin drugs.

[0023] In some embodiments, the anti- Abrus precatorius toxin includes treating, preventing, alleviating, and / or improving diseases or symptoms related to Abrus precatorius toxin poisoning. Among them, treatment refers to the treatment of patients with diagnosed Abrus precatorius toxin poisoning, prevention refers to the prevention of high-risk groups who may be exposed to the environment of Abrus precatorius toxin, and alleviation or improvement refers to the alleviation or improvement of diseases or symptoms related to Abrus precatorius toxin poisoning in patients with Abrus precatorius toxin poisoning.

[0024] In some embodiments, the pharmaceutically acceptable excipients and / or excipients include but are not limited to: stabilizers, preservatives, solubilizers, wetting agents, emulsifiers, buffers, sweeteners, colorants, salts for adjusting osmotic pressure, flavoring agents, masking agents, or antioxidants. In addition, by adding components that can delay the absorption of the active ingredient (i.e., Pladienolide B or its pharmaceutically acceptable salt as described above) to the drug, the absorption of the active ingredient in the drug can be prolonged.

[0025] In a second aspect, the present invention provides a pharmaceutical composition for anti- Abrus precatorius toxin, and the pharmaceutical composition contains Pladienolide B or its pharmaceutically acceptable salt described in the first aspect of the present invention.

[0026] In some embodiments, the pharmaceutical composition contains a therapeutically and / or prophylactically effective amount of Pladienolide B or its pharmaceutically acceptable salt described in the first aspect of the present invention. In other embodiments, the main active ingredient of the pharmaceutical composition is Pladienolide B or its pharmaceutically acceptable salt described in the first aspect of the present invention. In addition to the Pladienolide B or its pharmaceutically acceptable salt, the pharmaceutical composition may further contain other drugs that can be used for treating and / or preventing, or for assisting in treating and / or preventing diseases or symptoms related to Abrus precatorius toxin poisoning.

[0027] In some embodiments, the other drugs that can be used for treating and / or preventing, or for adjuvant treating and / or preventing abrin toxin poisoning-related diseases or symptoms include, but are not limited to: adsorbents (such as medicinal charcoal, etc.), antiemetics (such as metoclopramide, ondansetron, etc.), antidiarrheals (such as montmorillonite powder, etc.), hepatoprotective drugs (such as polyene phosphatidylcholine, reduced glutathione, etc.), kidney-protecting drugs (such as Shenkang injection, Bailing capsules, etc.), drugs for regulating electrolyte and acid-base balance (such as potassium chloride, sodium chloride, sodium bicarbonate, etc.), blood products (such as plasma, red blood cell suspension, etc.).

[0028] In the present invention, the other drugs that can be used for treating and / or preventing, or for adjuvant treating and / or preventing abrin toxin poisoning-related diseases or symptoms are not limited to the specific drugs listed above in the present invention. Any drug that may be able to be used for treating and / or preventing, or for adjuvant treating and / or preventing abrin toxin poisoning-related diseases or symptoms will fall within the protection scope of the present invention.

[0029] It should be noted that in the case where the present invention has clearly demonstrated through detailed cell experiments that Pladienolide B has an anti-abrin toxin toxic effect, those skilled in the art can know from common general knowledge that Pladienolide B or its pharmaceutically acceptable salts as described above in the present invention can achieve the present invention when used alone. Therefore, using Pladienolide B or its pharmaceutically acceptable salts as described above in the present invention alone, or using them in combination with other drugs will fall within the protection scope of the present invention.

[0030] In the third aspect, the present invention provides a drug preparation for anti-abrin toxin, and the drug preparation contains the pharmaceutical composition described in the second aspect of the present invention.

[0031] Furthermore, the dosage forms of the drug preparation include, but are not limited to: oral dosage forms, parenteral dosage forms, topical dosage forms.

[0032] In some embodiments, the oral dosage form refers to a dosage form in which the drug enters the gastrointestinal tract through oral administration and exerts its medicinal effect after absorption. The oral dosage forms include, but are not limited to: tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, emulsions.

[0033] Specifically, the tablet is a sheet-like preparation formed by pressing a mixture of the drug and excipients. It has the advantages of accurate dosage, good stability, high production efficiency, convenient administration, etc. It can be divided into various types such as ordinary tablets, coated tablets, chewable tablets, dispersible tablets, etc.

[0034] Specifically, the capsule formulations are divided into hard capsules and soft capsules. Hard capsules are prepared by filling drug powders or granules into hollow hard capsules; soft capsules are prepared by dissolving or suspending drugs in a suitable oily or non-oily liquid medium and then using the compression method or the dropping method. Capsule formulations can mask the unpleasant odor of drugs, improve drug stability, and are convenient to take.

[0035] Specifically, the granule formulations are dry granular preparations of drugs and suitable excipients with a certain particle size. They can be divided into soluble granules, suspension granules, effervescent granules, etc. Granule formulations are easy to dissolve, are absorbed relatively quickly, and are convenient to carry and take.

[0036] Specifically, the powder formulations are dry powder preparations of drugs and suitable excipients prepared by comminution and uniform mixing. Powder formulations have a small particle size, a large specific surface area, are easy to disperse, and have a fast onset of action, but relatively poor stability.

[0037] Specifically, the pill formulations are spherical or quasi-spherical preparations made from fine drug powders or extracts and suitable binders or other excipients. Depending on the excipients used and the preparation methods, they can be divided into honey pills, water pills, water-honey pills, paste pills, wax pills, etc.

[0038] Specifically, the syrup formulations refer to concentrated sucrose aqueous solutions containing drugs. Sucrose in syrup formulations can mask the bitter taste of drugs and at the same time has a certain preservative effect. It has a good taste and is especially suitable for children to take.

[0039] Specifically, the oral solution formulations are clear liquid preparations for oral administration made by dissolving drugs in suitable solvents. The drugs are uniformly dispersed in the solution, are absorbed quickly, and have a high bioavailability.

[0040] Specifically, the oral suspension formulations are non-uniform liquid preparations in which poorly soluble solid drugs are dispersed in a dispersion medium in the form of fine particles. In order to ensure the stability and uniformity of the drugs, excipients such as suspending agents and wetting agents are often added.

[0041] Specifically, the emulsion formulations are non-homogeneous liquid preparations in which two immiscible liquids are emulsified to form a liquid dispersed in the form of droplets in another liquid. Oral emulsion formulations can improve the taste and stability of drugs and increase the bioavailability of drugs.

[0042] In some embodiments, the parenteral dosage forms refer to dosage forms in which drugs are delivered into the body through other routes except oral administration. The parenteral dosage forms include but are not limited to: injections, aerosols, sprays, powder aerosols, suppositories, patches, implants.

[0043] Specifically, the injection is the most common parenteral dosage form, including solution injections, suspension injections, emulsion injections, sterile powders for injection, etc. It can be administered by intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, etc. Intravenous injection can enable the drug to quickly enter the blood circulation, exert its efficacy rapidly, and is suitable for emergency treatment and drugs that require rapid onset of action; the absorption rate of intramuscular injection and subcutaneous injection is relatively slow, but the drug efficacy can be maintained for a longer time.

[0044] Specifically, the aerosol is a preparation made by encapsulating the drug and a suitable propellant in a pressure-resistant container with a special valve system. When in use, the drug is sprayed out in a mist form by means of the pressure of the propellant, and acts by being inhaled through the respiratory tract or directly sprayed onto the mucosal surface of the cavity, skin and other parts. The aerosol has the effects of rapid onset and targeted action, the drug is evenly distributed, the local irritation of drug administration can be reduced, and it is convenient to use.

[0045] Specifically, the spray is a preparation in which a drug solution, emulsion or suspension is filled in a special device, and when in use, the content is released in a mist form by means of the pressure of a manual pump, high-pressure gas, ultrasonic vibration or other methods. It can be used for pulmonary inhalation, nasal mucosal administration, skin administration, etc.

[0046] Specifically, the powder aerosol includes inhalation powder aerosol, non-inhalation powder aerosol and topical powder aerosol. The inhalation powder aerosol is a preparation in which the patient actively inhales the atomized drug into the lungs; the non-inhalation powder aerosol is a preparation that uses a special dry powder administration device to spray the drug powder onto the mucosal surface of the cavity; the topical powder aerosol is a preparation that sprays the drug powder onto the skin or mucosal surface through a special device. The powder aerosol has the advantages of no propellant, good drug stability, accurate drug dosage, etc.

[0047] Specifically, the suppository is a solid preparation for human cavity administration made by mixing the drug with a suitable matrix. The commonly used one is the rectal suppository. After the suppository melts or dissolves in the cavity, the drug can be absorbed through the mucosa into the blood circulation, avoiding the first-pass effect of the liver, and is suitable for patients who are not suitable for oral administration.

[0048] Specifically, the patch includes transdermal patch and mucosal patch. The transdermal patch is a plaster made by evenly dispersing or dissolving the drug in a viscous matrix and coating it on a backing material, and the drug is slowly released through the skin into the blood circulation to play a systemic therapeutic role; the mucosal patch is a preparation applied to the mucosal surfaces such as the oral cavity, nasal cavity, and conjunctiva, and the drug exerts a local or systemic effect through mucosal absorption.

[0049] Specifically, the implant is a sterile solid preparation made by mixing the drug with excipients for implantation into the body. Generally, a special syringe is used to implant the implant into tissues such as subcutaneous or muscle of the human body, and the drug is slowly released, which can maintain an effective blood drug concentration for a long time and play a long-term therapeutic role.

[0050] In some embodiments, the topical dosage form refers to a dosage form that acts on local tissues to achieve a local therapeutic effect. The topical dosage forms include, but are not limited to: topical solutions, lotions, liniments, ointments, and gels.

[0051] Specifically, the topical solution is a clear liquid preparation for external use made by dissolving a drug in a suitable solvent.

[0052] Specifically, the lotion is a solution, emulsion, or suspension containing a drug, and is a preparation for cleaning or applying to intact skin.

[0053] Specifically, the liniment refers to a liquid preparation made by dissolving a drug in ethanol, oil, or a suitable solvent for rubbing on intact skin.

[0054] Specifically, the ointment is a uniform semi-solid external preparation made by mixing a drug with an oily or water-soluble matrix.

[0055] Specifically, the gel is a thick liquid or semi-solid preparation in the form of a homogeneous, suspension, or emulsion made by mixing a drug with an excipient capable of forming a gel. Topical gels are commonly used on the skin or mucosa.

[0056] In a fourth aspect, the present invention provides a method for in vitro non-therapeutically inducing cells to resist abrin toxin, the method comprising: treating a system in need thereof with Pladienolide B or a pharmaceutically acceptable salt thereof described in the first aspect of the present invention.

[0057] In some embodiments, the present invention places no particular limitation on the system in need thereof. Exemplarily, the system includes a cell system, subcellular system, tissue system, or organ system in need thereof.

[0058] In some embodiments, the cell system, subcellular system, tissue system, or organ system in need thereof is a system that needs to be induced to resist abrin toxin.

[0059] In some embodiments, for the specific dosage of Pladienolide B or a pharmaceutically acceptable salt thereof, those skilled in the art can make routine selections and adjustments according to the actual situation.

[0060] In a fifth aspect, the present invention provides a method for treating, preventing, alleviating, and / or improving diseases or symptoms related to abrin toxin poisoning, the method comprising: administering an effective amount of Pladienolide B or a pharmaceutically acceptable salt thereof described in the first aspect of the present invention, the pharmaceutical composition described in the second aspect of the present invention, and / or the pharmaceutical preparation described in the third aspect of the present invention to a subject in need thereof.

[0061] In some embodiments, the diseases or symptoms related to abrin poisoning include, but are not limited to: digestive system symptoms, liver injury, kidney injury, cardiovascular system symptoms, and nervous system symptoms caused by abrin poisoning.

[0062] In some embodiments, the digestive system symptoms caused by abrin poisoning include, but are not limited to: severe vomiting, diarrhea, abdominal pain, and gastrointestinal bleeding; the liver injury caused by abrin poisoning includes, but is not limited to: jaundice and abnormal liver function; the kidney injury caused by abrin poisoning includes, but is not limited to: oliguria or anuria, edema, and uremia; the cardiovascular system symptoms caused by abrin poisoning include, but are not limited to: arrhythmia and hypotension; the nervous system symptoms caused by abrin poisoning include, but are not limited to: headache, dizziness, fatigue, lethargy, and convulsions.

[0063] In some embodiments, the subject includes one or more animals, including, for example, cattle, horses, sheep, primates, avians, and rodent species. The subject can be a mammal, bird, fish, reptile, or amphibian. The mammal includes a human or non-human mammal. In other embodiments, the subject can be a mouse, rat, hamster, ferret, gerbil, rabbit, monkey, chimpanzee, horse, donkey, sheep, pig, chicken, goat, cat, or dog. In a preferred embodiment of the present invention, the subject is a human.

[0064] In some embodiments, the Pladienolide B or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or pharmaceutical preparation as described above of the present invention can be administered to the subject by oral administration, injection administration, or topical administration. For example, the method can include administering the Pladienolide B or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or pharmaceutical preparation as described above of the present invention to the subject three times a day, once a day, once every two days, etc. In other embodiments, the injection administration can include subcutaneous injection, intramuscular injection, intravenous injection, etc. In other embodiments, the injection administration can include directly injecting the Pladienolide B or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or pharmaceutical preparation as described above of the present invention into the body of the subject. In other embodiments, a combination of different administration methods can also be used. The present invention does not particularly limit the specific administration method, and those skilled in the art can make a conventional selection according to actual needs.

[0065] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0066] For the first time, the present invention creatively discovers that the compound Pladienolide B has an anti - abrin toxicity effect and can be used in the development of anti - abrin drugs. The present invention provides a theoretical basis for the research and development of anti - abrin drugs, opens up a new use of Pladienolide B, provides a brand - new method for treating or preventing abrin - poisoning - related diseases or symptoms, and has broad application prospects in the technical field of treating abrin - poisoning - related diseases or symptoms. Brief Description of the Drawings

[0067] Figure 1 Shows the effect of treating cells with different doses of Pladienolide B on the sensitivity to abrin;

[0068] Figure 2 Shows the effect of pre - treating cells with Pladienolide B for different times on the sensitivity to abrin. Among them, Figure A: pre - treatment time is 6 h; Figure B: pre - treatment time is 12 h; Figure C: pre - treatment time is 24 h. Detailed Embodiments

[0069] The following combines specific embodiments to further elaborate the present invention. The following specific embodiments are only used to explain the present invention and cannot be understood as a limitation to the present invention. Those of ordinary skill in the art can understand that: without departing from the principles and purposes of the present invention, various changes, modifications, substitutions, and variations can be made to these embodiments, and the scope of the present invention is defined by the claims and their equivalents. The experimental consumables, reagents, and raw materials used in the present invention are easily obtained by those of ordinary skill in the art. Without special instructions, they can all be obtained from commercial channels. The experimental methods without specific conditions described in the present invention are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers. In particular, the following embodiments are only used to illustrate the present invention and should not limit the scope of the present invention in any way. It should be noted that the experimental conditions and their results described in the following embodiments are only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0070] Example 1: Pladienolide B induces cells to be dose - dependent against abrin

[0071] 1. Experimental Method

[0072] In this example, after pre - treating Hela cells with different concentrations of Pladienolide B (PB or Pladi B) for 24 h, different concentrations of abrin were used for treatment. The IC50 of cells in the blank control DMSO group and the Pladienolide B pre - treatment group was compared to determine the cytotoxic effect of Pladienolide B against abrin - induced cells. The specific experimental method is as follows:

[0073] Cell viability was detected by CCK-8 assay: Hela cells were pretreated with 1, 6.25, 12.5, 25, 50 nM of the compound Pladienolide B for 24 h. The cells were passaged into 96-well plates. After the cells adhered, serum-free DMEM medium containing abrin at concentrations of 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125, 0 ng·mL -1 was added. Three replicates were set for each concentration (n = 3). After 24 h of abrin treatment, 10 μL of CCK-8 reagent was added to each well. The reaction was carried out at 37 °C for 2 h, and the absorbance was measured using a microplate reader at a wavelength of 450 nm. According to the formula: cell survival rate = [1 - (experimental well - control well) / (control well - blank well)] × 100%, the cell survival rates of the experimental wells at each concentration were calculated, and the survival curves were fitted and plotted.

[0074] 2. Experimental results

[0075] In this example, cells were pretreated with different doses of Pladienolide B for 24 h. After the cells pretreated with the compound Pladienolide B were treated with different concentrations of abrin for 24 h, the cell viability levels of each group were detected. The results are as Figure 1 shown. As can be seen from the Figure 1 results shown, pretreatment with 25 nM Pladienolide B could make the cells have a relatively obvious abrin tolerance effect. As the treatment concentration of Pladienolide B increased, the ability of the cells to resist abrin, especially to tolerate high concentrations of abrin, gradually increased, indicating that the effect of Pladienolide B in inducing cells to resist abrin was dose-dependent. Among them, when the cells were pretreated with 50 nM Pladienolide B, they showed a completely tolerant phenotype to 200 ng / mL of abrin, while the cell survival rate of the control group was only 1%. The above results indicate that Pladienolide B can effectively resist the toxicity of abrin and is dose-dependent, that is, this example proves that Pladienolide B has the effect of effectively inhibiting the toxicity of abrin and can be used in the preparation of anti-abrin drugs.

[0076] Example 2 Pladienolide B induces cells to resist abrin in a time-dependent manner

[0077] 1. Experimental method

[0078] In this example, it was further explored whether different pretreatment times of Pladienolide B affected the cell anti-toxin phenotype induced by it. The pretreatment time of 25 nM Pladienolide B on cells was set to 6, 12, and 24 h. The specific experimental methods are as follows:

[0079] Detection of cell viability by CCK-8 method: Hela cells were pretreated with 25 nM of the compound Pladienolide B for 6 h and 12 h. The cells were passaged into 96-well plates. After the cells adhered, serum-free DMEM medium containing abrin toxin at concentrations of 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125, 0.390625, 0.1953125, 0 ng·mL -1 was added. Hela cells were pretreated with 25 nM of the compound Pladienolide B for 24 h, and serum-free DMEM medium containing abrin toxin at concentrations of 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0 ng·mL -1 was added. For each concentration, 3 replicates were set (n = 3). After abrin toxin treatment for 24 h, 10 μL of CCK-8 reagent was added to each well, and the reaction was carried out at 37 °C for 2 h. The absorbance was measured using a microplate reader at a wavelength of 450 nm. According to the formula: cell survival rate = [1 - (experimental well - control well) / (control well - blank well)] × 100%, the cell survival rates of the experimental wells at each concentration were calculated, and the survival curves were fitted and plotted.

[0080] 2. Experimental results

[0081] In this example, the pretreatment time of 25 nM Pladienolide B on cells was set to 6, 12, and 24 h. When the pretreatment time of Pladienolide B was up to 6 h, there was no significant change in the sensitivity of the experimental group cells to abrin toxin compared with the DMSO control group cells ( Figure 2 A); when the pretreatment time of Pladienolide B was up to 12 or 24 h, abrin toxin had almost no killing effect on the cells ( Figure 2 B, 2C). The above results indicate that the effect of Pladienolide B in inducing cell resistance to abrin toxin has a certain time dependence.

[0082] The experimental results of Example 1 and Example 2 above show that Pladienolide B has an effective effect of inhibiting abrin toxin, can effectively induce cells to resist the toxic effect of abrin toxin, and has a certain dose dependence and time dependence.

Claims

1. Use of Pladienolide B or its pharmaceutically acceptable salt in the preparation of an anti-abrinia toxin drug, characterized in that: The structural formula of the Pladienolide B is shown in formula (I): Formula (I).

2. The use according to claim 1, characterized in that The pladienolide B has an anti-abrinia toxin toxicity effect.

3. The use according to claim 1, characterized in that The drug further comprises pharmaceutically acceptable excipients.

4. The use according to claim 3, characterized in that The pharmaceutically acceptable auxiliary material is an excipient.

5. The use according to claim 1, characterized in that: The dosage form of the drug is an oral dosage form, a parenteral dosage form or a topical dosage form.

6. The use according to claim 1, characterized in that: The dosage form of the drug is solution, powder injection, tablet, capsule, granule, powder, pill, powder spray or suspension.

7. The use according to claim 1, characterized in that The administration dosage of Pladienolide B or its pharmaceutically acceptable salt is 10 nM-100 mM.

8. The use according to claim 7, characterized in that The administration dosage of Pladienolide B or its pharmaceutically acceptable salt is 50 nM-100 nM.

9. A method for inducing cells to resist abrin toxin in vitro for non-therapeutic purposes, characterized in that: The method comprises: treating a system in need thereof with the Pladienolide B or a pharmaceutically acceptable salt thereof as claimed in claim 1.

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