CN115957212A - Application of schisandrin B in preparing medicine for preventing and treating coronavirus infection - Google Patents
Application of schisandrin B in preparing medicine for preventing and treating coronavirus infection Download PDFInfo
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- CN115957212A CN115957212A CN202111169495.7A CN202111169495A CN115957212A CN 115957212 A CN115957212 A CN 115957212A CN 202111169495 A CN202111169495 A CN 202111169495A CN 115957212 A CN115957212 A CN 115957212A
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Abstract
The invention belongs to the technical field of medicines, and relates to application of natural product Schisandrin B (Schizandrin B ) in preparation of a medicine for preventing and treating coronavirus infection. The innovation of the invention is that the schisandrin B has the function of inhibiting the replication of a novel coronavirus (SARS-CoV-2); has the effect of inhibiting replication of coronavirus HCoV-OC43 and HCoV-229E. The invention provides a scientific experimental basis for research and development of anti-coronavirus medicines and provides a new medicine treatment scheme for clinical prevention and treatment of coronavirus infectious diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a medicinal application of schisandrin B in preventing and treating coronavirus infectious diseases.
Background
New coronary pneumonia (COVID-19) is an infectious disease mainly characterized by the above respiratory tract infection caused by a novel coronavirus (SARS-CoV-2). There are 6505 clinical trials of Xinguan drugs (9/6/2021) on the Clinical Trials. Gov database in the United states, and no specific drug against SARS-CoV-2 has been found at present.
The emergence of variant strains of new coronavirus causes the protective power of the existing new coronavirus vaccines to be reduced to different degrees, so that the research on drugs for resisting the new coronavirus is still very urgent.
The prevention and treatment of these viral infections is challenging due to the lack of effective therapeutic modalities for the prevention and treatment of new coronaviruses (SARS-CoV-2), common coronaviruses (alphaviruses, betaviruses). Therefore, there is a need to find drugs with a broad spectrum of anti-coronavirus effects.
According to the report of the existing documents, the schisandrin B is an important effective component in the Chinese magnoliavine fruit which is a medicine and food homologous medicine, and has various pharmacological effects of liver toxicity resistance, cough relieving, lung injury protection, kidney injury protection, cardiovascular injury protection, nerve injury protection and the like. Has high consistency with the protection effect of Schisandrin B on organ tissue injuries such as lung injury, kidney injury, cardiovascular injury and nerve injury caused by coronavirus infection, and has protection effect on different organs caused by coronavirus infection.
Disclosure of Invention
The present invention relates to methods and results for the prevention and treatment of novel, common coronavirus infections of formula I.
It was found in this study that Schisandrin B (Schizandrin B ), herein referred to as compound I (LG 0056), exhibits antiviral activity against neocoronavirus (SARS-CoV-2), coronavirus (HCoV-OC 43) and coronavirus (HCoV-229E).
The invention solves the technical problem of providing the function of schisandrin B or pharmaceutically acceptable salt thereof in preparing medicaments for preventing and treating coronavirus infectious diseases.
Specifically, in order to solve the technical problem of the invention, the following technical scheme is adopted:
the first aspect of the technical proposal of the invention provides the application of schisandrin B shown in structural formula I or pharmaceutically acceptable salt thereof in preparing the medicine for preventing or treating coronavirus infection,
the pharmaceutically acceptable schisandrin B salt comprises pharmaceutically acceptable organic salt or inorganic salt, wherein the organic salt comprises sulfonate, carboxylate, amino acid salt and fatty acid salt, and the inorganic salt comprises hydrochloride, bromate, iodate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate and nitrate.
The sulfonate comprises alkyl sulfonate containing 1-15 carbon atoms, benzene sulfonate, p-toluene sulfonate, o-toluene sulfonate and m-toluene sulfonate; carboxylates include tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate and aspartate; the fatty acid salt comprises a long chain fatty acid salt having 2 to 18 carbon atoms.
Wherein the coronavirus comprises novel coronavirus SARS-CoV-2 and novel coronavirus COVID-19 induced by the coronavirus SARS-CoV-2.
The coronavirus infection comprises infectious diseases induced by HCoV-OC43 and HCoV-229E coronavirus.
The second aspect of the technical scheme of the invention provides an application of a pharmaceutical composition in preparing a medicament for preventing or treating coronavirus infection, wherein the pharmaceutical composition comprises schisandrin B shown in a structural formula I or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient,
general description
The invention is first described in detail with reference to the noun terms that are used to facilitate a better understanding of the invention.
The term "antiviral drug" as used herein refers to a drug (compound, crude extract or biological agent) effective in inhibiting the formation or replication of a virus in a human body, including but not limited to drugs that interfere with host proteins or viral mechanisms necessary for the virus during the formation or replication of the human body.
"prevention" (prevention) refers to any treatment that prevents further progression of a disease or disorder. The term "preventing" also includes the use of a therapeutically effective amount of a compound or composition of the invention prior to exposure of an individual to a virus (i.e., pre-exposure prevention) to prevent the symptoms of disease from developing and/or to prevent the virus from reaching detectable levels in a sample of the patient's virus.
"treating" (or treating) means reversing, alleviating, or inhibiting one or more symptoms of the disease for which prevention is indicated. In certain embodiments, "treatment" refers to a compound or composition according to the present invention to reduce or eliminate symptoms of viral infection and/or reduce the viral load of a patient's viral sample.
The term "pharmaceutical composition" refers to a pharmaceutical composition prepared by mixing the compound of the present invention with adjuvants or other active ingredients in any ratio.
The compound names provided above are named according to literature, and one skilled in the art will appreciate that other recognized naming systems and symbols can be used to name or identify the compound structure. For example, a compound may be named or identified by a generic name, a systematic or non-systematic name. Commonly accepted nomenclature systems and symbols in the chemical arts include, but are not limited to, the Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC).
The beneficial technical effects are as follows: the research discovers that schisandrin B has broad-spectrum antiviral effect, including novel coronavirus (SARS-CoV-2), coronavirus HCoV-OC43 and HCoV-229E, and has good clinical application prospect.
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FIG. 1 is a graph showing the pharmacodynamic effect of LG0056 against neocoronaviral-induced cytopathies.
Detailed Description
Experimental example 1 evaluation of Schisandrin-B Effect against novel coronavirus (SARS-CoV-2)
Cell: veroE6 cells.
The virus strain: SARS-CoV-2, titer TCID 50 ＝10 -6 100 mu L, stored at 80 ℃ by the health quarantine research institute of Guangzhou customs technology center/national biosafety detection key laboratory (respiratory disease key laboratory high pathogenic microorganism research laboratory). The virus titer of 100TCID was used 50 。
Experimental materials and methods:
(1) Sample treatment: the sample concentration in DMSO, 10mg/ml, was used as stock solution. The drug was diluted with virus culture medium just before use, the first concentration was 100. Mu.g/ml, and 5 dilutions were made in the culture medium, each at 5 dilutions. The virus control group is SARS-CoV-2 virus liquid, and the positive drug is Reidesivir (Redesivir).
(2) And (3) evaluating the toxicity of the sample: veroE6 cells in exponential growth phase are spread in a 96-well cell culture plate (cell number 2X 10) 4 One/hole). After they have grown to a monolayer of cells, the serum-containing medium is aspirated and 90. Mu.L of serum-free medium is added to each well. Samples dissolved in DMSO at concentration A (concentration 10 mg/mL) were diluted to 1mM in physiological saline, two-fold. 10 μ L of each concentration sample was added to a VeroE6 monolayer while a normal control without drug was set. 37 ℃ and 5% of CO 2 Observing cell morphology under microscope after growing for 48h, and simultaneously performing MTT staining on cells to examine cell viability to obtain cell viability (OD) of each sample sample / OD normal *100%, normal control group, sample group), and the median Toxicity Concentration (TC) of the drug to the cells was calculated 50 ) And maximum nontoxic concentration (TC) of drug 0 ) And provides experimental basis for evaluating antiviral efficacy.
(3) Sterile 96-well culture plate, 100. Mu.L of 2X 10 concentration per well 5 cells/mL VeroE6 cells, 37 ℃ 5% CO 2 Culturing for 24 hours;
(4)adding 100TCID into culture plate experimental group and virus control group 50 Virus fluid 100 μ L/well, 37 ℃ 5% 2 Adsorbing for 2 hours by an incubator;
(5) After 2h, discarding the cell culture solution in the 96-well culture plate; diluting the tested medicine into each concentration in table 1, wherein each concentration is 3 multiple holes, and adding the liquid medicine into each hole with the concentration of 100 mu l;
(6) Simultaneously setting a cell control, a blank control (solvent control), a virus control (negative control) and a positive drug control;
(7) Cell 37 ℃,5% CO 2 Incubating in an incubator for 3 days;
(8) Cytopathic effect (CPE) was observed under an optical microscope and the degree of cytopathic effect was recorded according to the following 6-point scale: "-" no lesions appeared; "±" means less than 10% cytopathic effect; "+" is about 25% of the cellular pathology; "+ +" indicates about 50% of cellular pathology; "+++" indicates that about 75% of the cells are diseased: "+ ++" indicates that 75% or more of the lesions are diseased. The half maximal effective concentration (IC) was calculated using the Reed-Muench method or GraphPad prism5.0 50 ). And (3) judging the drug effect standard: concentrations that inhibit viral CPE by 50% are considered effective concentrations.
(9) The experimental conditions are as follows: the above experimental operations were all completed in the BSL-3 laboratory.
The experimental results are shown in table 1, and the efficacy graph is shown in fig. 1, wherein the abscissa concentration is concentration, and the ordinate inhibition (% of control) refers to the inhibition rate of the drug on the virus.
The result shows that schisandrin B has obvious effect of resisting new coronavirus, EC 50 =8.62 mug/ml, has activity similar to that of the positive drug Remdesivir (Remdesivir), and provides a new scheme for clinical treatment of new coronary pneumonia.
TABLE 1 Schizandrin B inhibition of cytopathic effect induced by novel coronavirus SARS-CoV-2 on in vitro VeroE6 cells
a TC 50 Average 50% cytotoxic CompoundConcentration of substance
b EC 50 Concentration of average 50% inhibition
c SI selection index, TC 50 /EC 50 .
Experimental example 2 evaluation of Schisandrin-B Activity against coronavirus HCoV-OC43
H460 cells were used as virus hosts, and the extent of cytopathic effect (CPE) of the sample on the virus-induced cells was determined. The virus strain: the coronavirus HCoV-OC43 is stored at-80 ℃. Sample treatment: samples were made up to stock solution with DMSO concentration of 10mg/ml and 3-fold dilutions were made in culture medium, 8 dilutions each. Positive control drug: ribavirin (RBV), hubei Tian Yao pharmaceutical industry Co., ltd. (batch No. 31712252).
The test method comprises the following steps: h460 cells were seeded into 96-well plates and 5% CO 2 And cultured at 37 ℃. After 24 hours the infection is approximately 100TCID 50 The coronavirus of (1), simultaneously adding a maintenance solution containing samples of different dilutions and a positive control drug, simultaneously setting a cell control well and a virus control well, 5% 2 And cultured at 37 ℃. Observing the pathological change degree (CPE) of each group of cells when the pathological change degree (CPE) of the virus control group reaches 4+, and respectively calculating the half Toxic Concentration (TC) of the sample to the cells by using a Reed-Muench method 50 ) And half inhibitory concentration (EC) against virus 50 ). The results are shown in Table 2.
The results show that the schisandrin B resists the EC of coronavirus HCoV-OC43 50 =34.67 mug/ml, the activity is similar to that of the positive medicine ribavirin, which indicates that the schizandrin B has obvious effect of resisting coronavirus HCoV-OC 43.
TABLE 2 Schizandrin B inhibitory Effect on coronavirus HCoV-OC 43-induced cytopathic Effect on H460 cells in vitro
a TC 50 Average 50% cytotoxic compound concentration
b EC 50 Concentration of average 50% inhibitionDegree of rotation
c SI selection index, TC 50 /EC 50 .
Experimental example 3 evaluation of Schisandrin-B Activity against coronavirus HCoV-229E
Huh7 cells are taken as virus hosts, and the degree of cytopathic effect (CPE) caused by virus inhibition of a sample is determined. The virus strain: the coronavirus HCoV-229E was stored at-80 ℃. Samples were made up as stock solutions in DMSO at a concentration of 10mg/ml. The culture medium was further diluted 3-fold, 8 dilutions each. Positive control drug: ribavirin (RBV), hubei Tian Yao pharmaceutical industry Co., ltd. (batch No. 31712252).
The test method comprises the following steps: inoculation of Huh7 cells into 96-well culture plates, 5% CO 2 Culturing at 37 ℃. After 24 hours the infection is approximately 100TCID 50 The coronavirus of (1), simultaneously adding a maintenance solution containing samples of different dilutions and a positive control drug, simultaneously setting a cell control well and a virus control well, 5% 2 And cultured at 37 ℃. Observing the pathological change degree (CPE) of each group when the pathological change degree (CPE) of the virus control group reaches 4+, and respectively calculating the half Toxic Concentration (TC) of the sample to the cells by using a Reed-Muench method 50 ) And half inhibitory concentration (EC) against virus 50 ). The results are shown in Table 3.
The results show that schisandrin B resists EC of coronavirus HCoV-229E 50 The activity of the medicine is equivalent to that of a positive medicine ribavirin, namely 4.32 mu g/ml, so that the schisandrin B has a remarkable effect of resisting coronavirus HCoV-229E.
TABLE 3 Schizandrin B inhibition of coronavirus HCoV-229E-induced cytopathic effects on in vitro Huh7 cells
a TC 50 Average 50% cytotoxic compound concentration
b EC 50 Concentration of average 50% inhibition
c SI selection index, TC 50 /EC 50 .
In conclusion, the schisandrin B has various pharmacological effects such as hepatotoxicity resistance, cough resistance, lung injury protection, kidney injury protection, cardiovascular injury protection, nerve injury protection and the like reported in documents, also has obvious effects of resisting novel coronavirus SARS-CoV-2 and coronavirus HCoV-OC43 and HCoV-229E, has broad-spectrum coronavirus infection resistance, and is expected to become an effective treatment medicament for preventing and treating coronavirus infectious diseases.
Claims (6)
1. The application of schisandrin B shown in formula I or pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating coronavirus infection,
2. the use according to claim 1, wherein the pharmaceutically acceptable salt comprises a pharmaceutically acceptable organic salt or inorganic salt, wherein the organic salt comprises a sulfonate, a carboxylate, an amino acid salt, and a fatty acid salt, and the inorganic salt comprises a hydrochloride, a bromate, an iodate, a sulfate, a hydrogen sulfate, a phosphate, a hydrogen phosphate, a dihydrogen phosphate, and a nitrate.
3. Use according to claim 2, characterized in that said sulfonates comprise alkylsulfonates containing 1-15 carbon atoms, benzenesulfonates, p-toluenesulfonates, o-toluenesulfonates, m-toluenesulfonates; carboxylates including tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate, aspartate; the fatty acid salt comprises a long chain fatty acid salt having 2 to 18 carbon atoms.
4. Use according to claim 1, characterized in that said coronavirus infection is selected from the group consisting of the novel coronavirus SARS-CoV-2 and infectious diseases induced by it.
5. Use according to claim 1, wherein the coronavirus infection is selected from the group consisting of HCoV-OC43, HCoV-229E and infectious diseases induced thereby.
6. An application of a pharmaceutical composition in preparing a medicament for preventing or treating coronavirus infectious diseases is characterized in that the pharmaceutical composition comprises schisandrin B shown in a structural formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient,
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103156921A (en) * | 2011-12-13 | 2013-06-19 | 天津市国际生物医药联合研究院 | Application of schisandra chinensis and extracts of schisandra chinensis in resisting severe acute respiratory syndrome (SARS) coronavirus infection |
| KR20210014601A (en) * | 2019-07-30 | 2021-02-09 | 한국 한의학 연구원 | Composition for preventing or treating coronavirus infection |
| CN113304200A (en) * | 2021-03-09 | 2021-08-27 | 中国科学院武汉病毒研究所 | New application of schisandra extract |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103156921A (en) * | 2011-12-13 | 2013-06-19 | 天津市国际生物医药联合研究院 | Application of schisandra chinensis and extracts of schisandra chinensis in resisting severe acute respiratory syndrome (SARS) coronavirus infection |
| KR20210014601A (en) * | 2019-07-30 | 2021-02-09 | 한국 한의학 연구원 | Composition for preventing or treating coronavirus infection |
| CN113304200A (en) * | 2021-03-09 | 2021-08-27 | 中国科学院武汉病毒研究所 | New application of schisandra extract |
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