CN115707464A - Inhibition of schaftoside on novel coronavirus main protease and medicinal application thereof - Google Patents
Inhibition of schaftoside on novel coronavirus main protease and medicinal application thereof Download PDFInfo
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- CN115707464A CN115707464A CN202110954400.6A CN202110954400A CN115707464A CN 115707464 A CN115707464 A CN 115707464A CN 202110954400 A CN202110954400 A CN 202110954400A CN 115707464 A CN115707464 A CN 115707464A
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Abstract
The invention discloses a new medical application of a flavone C-glycoside compound schaftoside existing in liquorice. The invention discovers that schaftoside can effectively inhibit novel coronavirus main protease (3 CL) pro ) The compound has good affinity to the coronavirus, and simultaneously, the compound is proved to have high-efficiency inhibitory effect on the novel coronavirus, so that the compound is a green candidate inhibitor of the novel coronavirus. Based on the above findings, schaftoside and its pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs and mixtures thereof can be used for preparing medicines and health products for treating and/or preventing novel coronavirus or other coronavirus infection.
Description
Technical Field
The invention relates to a new medicinal use of schaftoside, in particular to the use of schaftoside in resisting novel coronavirus main protease (3 CL) pro ) The use of (1).
Background
The novel coronavirus was named SARS-CoV-2 by the World Health Organization (WHO) at 12/1/2020 and 2019, and subsequently, the novel coronavirus pneumonia was named COVID-19 at 11/2/2020. By 8 days 2021, over 400 million deaths had occurred in the whole world. However, at present, no specific medicine aiming at COVID-19 exists.
The novel coronavirus SARS-CoV-2 is a member of the Sarbecovirus subspecies (Beta-CoV lineage B), and the genome encodes four structural proteins as well as the common coronavirus: spike protein (S protein), envelope protein (E protein), membrane protein (M protein) and nucleocapsid protein (N protein). The generation of these four major structural proteins relies on the use of a host protease (3 CL) pro ) Cleaved nonstructural protein nsp1. Further, 3CL pro Has clear biological functions and important enzyme active sites, and can be used as the most important target for developing small molecule inhibitors.
Radix Glycyrrhizae (Glycyrrhizae Radix et Rhizoma) is a commonly used Chinese medicine, has pharmacological activities of protecting liver, resisting ulcer, resisting virus, resisting oxidation, resisting inflammation, resisting bacteria, resisting malaria, etc., and contains chemical components such as flavone, flavonoid glycoside, triterpene saponin, etc. Wherein, the flavone C-glycosides in licorice are widely distributed in plants, and the natural products with special structure types have good biological activity. For example, vitexin (apigenin 6-C-glucoside) and isovitexin (apigenin 8-C-glucoside) in Scutellariae radix have good antiviral effect; orientin (luteolin 8-C-glucoside) and isoorientin (luteolin 8-C-glucoside) in Adhatoda vasica of India nationality have good pharmacological action; puerarin (daidzein 8-C-glucoside), an index component in radix Puerariae, has a good effect of treating cardiovascular diseases, and is currently applied to clinical application. Flavonoid anthraquinone compounds such as Soyflower and Aloe-emodin have been reported to inhibit SARS major protease (Chao PDL et al, antiviral Research 2005, 68, 36-42). Furthermore, constituents such as vitexin and orientin have activities against novel coronavirus main proteases (Shunmugiah KP et al, journal of biololer Structure & Dynamics 2020). Therefore, the discovery of effective novel antiviral drugs from traditional natural drugs has important practical significance and good application prospect.
Schaftoside is a flavone C-glycoside component in liquorice, glycosyl of the flavone C-glycoside component is mostly substituted on carbon C (6) or carbon C (8) of a flavone mother nucleus, and the components mostly have pharmacological activities of resisting inflammation, resisting oxidation and the like, but the activity of resisting new corona viruses is not reported.
Disclosure of Invention
The present invention aims to provide a medicament for the prevention and/or treatment of novel coronavirus and other coronavirus infections. The research of the invention finds that schaftoside has main protease (3 CL) to coronavirus pro ) Has inhibitory effect, and can be used for inhibiting coronavirus activity. Therefore, the invention provides a new application of the glycyrrhiza extract schaftoside in inhibiting coronavirus main protease.
The structural formula of the compound is as follows:
the schaftoside is a flavone dicarboside compound, and the compound per se or at least one of pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer and prodrug thereof, and a mixture thereof, and can inhibit main protease (3 CL) of coronavirus pro ) Can be used for preventing and/or treating infection of novel coronavirus or other coronavirus.
The medicine for preventing and/or treating coronavirus infection, which is prepared by taking the active compound or pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, prodrug and mixture thereof as an active ingredient, also belongs to the protection scope of the invention.
When necessary, one or more pharmaceutically acceptable carriers or auxiliary materials can be added into the medicine. The carrier or the auxiliary material comprises a diluent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant and the like which are conventional in the pharmaceutical field.
The active compound or pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers and prodrugs thereof are used as active ingredients, and are used alone or in combination, or are matched with other medicines, auxiliary materials and the like to prepare various dosage forms, including but not limited to tablets, powder, pills, injections, capsules, films, suppositories, electuary, granules and other forms. The medicaments in various dosage forms can be prepared according to the conventional method in the field of pharmacy.
The schaftoside provided by the invention is a flavone compound in liquorice, and the ingredients mostly have pharmacological activities of anti-inflammation, anti-immunity, anti-tumor, anti-oxidation and the like, but the anti-new coronavirus activity of the schaftoside is not reported. The invention discovers for the first time that schaftoside has an inhibiting effect on main protease of coronavirus, thereby playing a role in resisting coronavirus activity, and can be used for preparing medicines or health-care products for treating and/or preventing coronavirus infection.
Drawings
FIG. 1 shows the detection of schaftoside on new coronavirus main protease (3 CL) in example 1 pro ) Experimental results of inhibition rates.
FIG. 2 is the result of experiment for testing the inhibition rate and cytotoxicity of schaftoside against the novel coronavirus in example 2.
FIG. 3 is an immunofluorescence assay of schaftoside (10. Mu.M and 30. Mu.M) of example 3 against the novel coronavirus.
FIG. 4 shows example 4 pairs of schaftoside against novel coronavirus main protease (3 CL) pro ) Of (2) affinityAnd (5) detecting the force.
Detailed Description
The present invention is further illustrated below with reference to examples, which are to be understood as merely illustrative and not limitative of the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 schaftoside and New coronavirus Main protease (3 CL) pro ) Detection of inhibition ratio of
1. Test materials and methods
Measurement of SARS-CoV-2 3CL by the fluorogenic substrate Dabcyl-KTSAVLQSGFRKME-Edans pro Proteolytic activity of (a). The activity was detected by monitoring 535nm wavelength 340nm emitted fluorescence. The final concentration of protein was 12.5. Mu.g/mL, the concentration of schaftoside in compound samples was 1, 2, 4, 8, 16. Mu.M, the buffer was 20mM TRIS-HCl (pH 7.0), and the substrate concentration was 3mM. The reaction conditions were 25 ℃ for 10 minutes. The enzyme activity was calculated according to the following equation:
A＝enzyme activity,df＝difution factor,ΔOD＝absorptionchange/min,
V s ＝sample volume,C＝concentration.
wherein A represents enzyme activity, df represents dilution factor, Δ OD represents absorbance change, and V s Represents the sample volume and C represents the protein concentration.
2. Results of the experiment
Schaftoside for new type coronavirus main protease (3 CL) pro ) Has better inhibitory activity. IC (integrated circuit) 50 The value was 1.57. + -. 0.22. Mu.M, as shown in FIG. 1.
Example 2 inhibition Rate and cytotoxicity of schaftoside against novel Coronaviridae
1. Test materials and methods
In live virus model activity screening, SARS-CoV-2 was administered simultaneously to Vero E6 cells infected at a ratio of MOI =0.1 (MOI is the number of viruses per cell). After incubation for 2 hours, the cytotoxicity of the compound was tested using a CCK-8 kit; compound antiviral activity was assessed by qPCR testing for viral copy number.
2. Results of the experiment
In the new coronavirus active virus system, schaftoside can inhibit virus infection, IC 50 11.83. Mu.M, as shown in FIG. 2.
Example 4 immunofluorescence assay of schaftoside against novel coronaviruses
1. Test materials and methods
Vero E6 cells were incubated on glass slides for 24 hours. The compound schaftoside was added to the cells at concentrations of 10 μ M and 30 μ M with the virus solution. After 24 hours post infection, cells were treated with 4% paraformaldehyde for 15 minutes at room temperature. Cells were incubated with a 1. After a thorough wash for 15 minutes, unbound antibody was removed. Cells were then incubated with 1. Slides were washed, nuclear stained with DAPI (Sigma) after 15 minutes, and imaged with confocal fluorescence microscopy (UltraVIEW VoX; perkinElmer, usa).
2. Results of the experiment
Schaftoside was able to inhibit the novel coronavirus infection as shown in figure 3.
Example 4 schaftoside and New coronavirus Main protease (3 CL) pro ) Affinity detection of
1. Test materials and methods
Detection of candidate drug and new coronavirus main protease (3 CL) by Surface Plasmon Resonance (SPR) system pro ) The affinity of (a). Protein 3CL by standard primary amine coupling reactions pro Immobilized on a sensor chip CM5, the instrument uses Biacore 8K. SARS-CoV 3CL pro Diluted in 10mM ammonium acetate (pH 4.5) and allowed to standThe final concentration was 25. Mu.g/mL. 5% DMSO and 0.05% P20 in PBS as buffer. Final SARS-CoV 3CL pro Typically about 12000RU. To study binding of schaftoside at different concentrations, the buffer was run for 60s binding and 60s dissociation at a flow rate of 30 μ L/min. Equilibrium dissociation constant (K) for assessing protein-ligand binding affinity was determined by steady-state affinity method fitting analysis of Biacore data D )。
2. Results of the experiment
The results of surface plasmon resonance detection show that schaftoside is used for treating the new crown major protease (3 CL) pro ) Has a good affinity of D The value is 1.24X 10 -5 As shown in fig. 4.
Claims (7)
1. The application of at least one of schaftoside and pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer and prodrug thereof in preparing medicaments or health care products for preventing and/or treating coronavirus infection is disclosed, wherein the formula of the schaftoside is shown as follows:
2. the use according to claim 1, wherein the coronavirus is the novel coronavirus SARS-CoV-2.
3. A medicine or health product for preventing and/or treating coronavirus infection contains at least one of schaftoside and pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer and prodrug thereof as effective component, wherein the formula of schaftoside is shown as follows:
4. the pharmaceutical or nutraceutical product of claim 3, wherein said coronavirus is the novel coronavirus SARS-CoV-2.
5. The medicament or health product of claim 3, further comprising one or more pharmaceutically acceptable carriers or excipients.
6. At least one of schaftoside and pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer and prodrug thereof as coronavirus main protease 3CL pro Wherein, the structural formula of the schaftoside is shown as follows:
7. the use according to claim 6, wherein the coronavirus main protease 3CL is pro Is the main protease 3CL of a novel coronavirus pro 。
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| CN117442603A (en) * | 2023-12-14 | 2024-01-26 | 海南医学院 | Application of schaftoside in preparation of heart failure resistant medicines |
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