CN114617895A - Application of tannic acid in preparing anti-coronavirus medicine and medicine - Google Patents
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to application of tannic acid in preparation of a coronavirus infection resisting medicine. The tannic acid has strong inhibition effect on the enzyme activity of a target main protease 3Clpro of coronavirus, particularly novel coronavirus, and can be used for preparing a medicament for resisting coronavirus infection, particularly novel coronavirus infection.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to application of tannic acid in preparation of a coronavirus infection resisting medicine
Background
Coronaviruses belong to the single positive strand RNA virus, and the family of coronaviruses mainly includes novel coronaviruses (SARS-CoV-2), SARS coronaviruses (SARS-CoV), middle east respiratory syndrome coronaviruses (MERS-CoV), HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU. Coronaviruses commonly cause respiratory and intestinal diseases, neurological symptoms, and myocarditis. In 2003, severe upper respiratory disease (SARS) outbreaks, infected with about 8000 people worldwide, with mortality rates as high as 10%. In 2014, Middle East Respiratory Syndrome (MERS) was outbreak in many countries around the world with mortality rates higher than SARS-CoV, reaching approximately 40%. By the end of 2019, a novel coronavirus (Covid-19) is exploded, the death rate of the novel strain (SARS-CoV-2) is lower than that of SARS-CoV-1 in 2003, but the novel strain has stronger infection capacity, so far, the number of infected people worldwide is 1000 thousands, the death rate is nearly 100 thousands, and the epidemic situation is continuously fermented. The infection of these diseases seriously affects the health of people. The repeated outbreaks of coronaviruses suggest that human beings are poorly informed about their research and the development of drugs for treating new coronaviruses is imminent.
The main protease of coronavirus, also called 3C-like protease (3CLpro), is a hydrolase expressed in the genome nsp5 at the 5' end of coronavirus and mainly functions to cleave at least 11 sites on the polyproteins pp1a and pp1ab, which need to be processed into mature functional protein after hydrolysis; the 3C-like protease (3CLpro) is a cysteine protease that recognizes sequences with Leu and Glin at positions P2 and P1, respectively. In addition, the substrate binding site of the 3C-like protease (3CLpro) is highly conserved and plays a key role in mediating virus replication and transcription, so the 3CL protease can be used as an ideal target point for designing and screening anti-coronavirus medicines.
Tannic acid is a novel hERG channel blocker, IC50It was 3.4. mu.M. Tannic acid modulates NF κ B signaling pathway by modulating PPAR γ expression for the treatment of allergic dermatitis (atopic dermatitis AD). In the AD mouse model, tannic acid treatment increased PPAR γ expression in AD skin sections. In a vehicle-induced AD mouse model, PPAR γ protein expression was inhibited, but PPAR γ protein expression increased dramatically when treated with tannic acid. The expression of IL-1 β, TNF α, TNFR1 and COX2 proteins was significantly upregulated in a mouse model where the vehicle caused AD, but IL-1 β, TNF α, TNFR1 and COX2 showed downregulation after tannic acid treatment. Here we demonstrate that tannic acid can inhibit the enzymatic activity of the main protease 3Clpro of coronaviruses, especially of novel coronaviruses. Through examining the relevant data, no report about tannin as a coronavirus main protease 3Clpro inhibitor is found.
Disclosure of Invention
The invention aims at the problem that relevant inflammatory diseases such as lung, respiratory tract and intestinal tract diseases, nervous system symptoms, myocarditis and the like caused by coronavirus lack of effective prevention and treatment medicines, and points out the application of tannic acid in preparing the anti-coronavirus inflammation medicines.
The invention aims to provide a tannin as an inhibitor of coronavirus 3C-like protease (3CLpro) and application thereof in preparing a medicament for preventing and/or treating novel coronavirus infection. The technology of the invention is based on the three-dimensional structure of the novel coronavirus 3CLpro to carry out drug design, and thousands of compounds including a natural product library, a clinical compound library and an antiviral drug library are virtually screened to obtain the compound which can possibly inhibit the novel coronavirus 3 CLpro. We then performed enzyme activity assays using a commercially available 3CLpro fluorescent probe construction method and used for inhibitor screening.
By screening the medicines according to the scheme, the invention discovers that the compounds shown in the following general formula 1 have the inhibition effect on SARS-CoV-23 CL protease:
the compound has obvious effect of inhibiting novel coronavirus 3C-like protease (3CLpro), and IC502.439uM. shows that the compound can effectively inhibit the activity of the novel coronavirus 3C-like protease. Furthermore, given the high similarity of coronavirus main proteases reported in the literature, we theorize that this class of compounds is also effective in inhibiting the activity of other coronavirus main proteases, especially for SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU. Preferably, tannic acid having an inhibitory effect also includes various optical isomers, hydrates thereof and pharmaceutically acceptable salts thereof with acids. The compounds of formula I can be used in combination with pharmaceutically acceptable adjuvants for the preparation of medicaments for the treatment and prophylaxis of novel coronavirus infections. The adjuvant comprises diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, and synergist. The medicine can be made into injection, tablet, pill, capsule, suspension or emulsion. The administration route can be oral, percutaneous, intravenous or intramuscular injection.
Drawings
FIG. 1 is a graph showing the time-dependent trend of the fluorescence intensity of the substrate peptide under 3C-like protease metabolism at different concentrations of the inhibitor tannic acid in example 1
FIG. 2 is a graph of the inhibition of the novel coronavirus 3C-like protease by tannic acid, an inhibitor of example 2.
Detailed Description
In order to illustrate the invention more clearly, the following examples are given for the purpose of illustrating the invention more clearly and are not to be construed as limiting the invention.
In carrying out the experiment, all the procedures and procedures, reaction conditions of the substrate, and the like are designed and carried out according to methods well known to those skilled in the art.
In the following examples, we used inhibitor molecules, available from mce (medchemeexpress) or other common commercial sources.
SARS-Cov-23C-like protease used in the present invention is purchased from CrystalO Biopharma, substrate Dabcyl-KTSAVLQ ↓.SGFRKM-E (Edans) -NH2 is purchased from GL biochem, and Borax borate buffer is purchased from Lei root organisms.
Preferably, SARS-Cov-23C-like protease (concentration 0.1mg/mL), substrate peptide Dabcyl-KTSAVLQ ↓ ] SGFRKM-E (Edans) -NH2 (concentration 0.1mM-5mM), borax borate buffer (pH ═ 5-8), the concentration of borax borate buffer is 10-100 millimole/liter.
The invention requires fluorescence detection with a fluorescence microplate reader.
Example 1: determination of inhibitory Activity of tannic acid against SARS-Cov-23C-like protease
The specific implementation process comprises the following steps:
1) storing the SARS-Cov-23C-like protease and substrate peptide stock solution in a refrigerator at-80 ℃;
2) thawing SARS-Cov-23C-like protease (concentration 0.1mg/mL) in a frozen plate (-4 to 4 ℃) at room temperature, diluting 1uL in 98uL borax borate buffer (pH 7.4), and adding into the detection plate;
3) adding 1uL of inhibitor (tannic acid, concentration of 0, 0.025mM, 0.125mM, 0.25mM, 0.5mM, 1mM, 2.5mM) at different concentrations into the solution obtained in the step (2);
4) adding 1uL of substrate peptide (0.5mM) with the same concentration into the solution obtained in the step (3), incubating at 37 ℃ by using a fluorescence microplate reader, monitoring 342nm excitation by using the fluorescence microplate reader, detecting the fluorescence emission value at 496nm while incubating, and taking one point every 1 minute;
5) the effect of the slow increase of the fluorescence intensity of the substrate peptide under the enzyme metabolism with time in the presence of the inhibitors at different concentrations is shown in FIG. 1 below, and the results show that the increase of the fluorescence of the substrate peptide under the enzyme metabolism can be inhibited by the inhibitor tannic acid, and that the inhibition is increased with the increase of the inhibitor concentration.
Example 2: determination of the ability of tannic acid to inhibit SARS-Cov-23C-like protease
The specific implementation process is as follows:
1) storing the SARS-Cov-23C-like protease and substrate peptide stock solution in a refrigerator at-80 ℃;
2) thawing SARS-Cov-23C-like protease (concentration 0.1mg/mL) in a frozen plate (-4 to 4 ℃) at room temperature, diluting 1uL in 98uL borax borate buffer (pH 7.4), and adding into the detection plate;
3) adding 1uL of inhibitor (tannic acid, concentration of 0, 0.025mM, 0.125mM, 0.25mM, 0.5mM, 1mM, 2.5mM) at different concentrations into the solution obtained in the step (2);
4) adding 1uL of substrate peptide (0.5mM) with the same concentration into the solution obtained in the step (3), incubating at 37 ℃ by using a fluorescence microplate reader, monitoring 342nm excitation by using the fluorescence microplate reader, detecting the fluorescence emission value at 496nm while incubating, and incubating for 1 h;
5) and counting the fluorescence emission value at 496nm after 342nm excitation before and after incubation of each group. The fluorescence change values before and after incubation of the control group (inhibitor concentration 0 group) were taken as 100, and the fluorescence change values before and after incubation of the different inhibition groups were compared to obtain the residual activity value (residual activity). The logarithmic value of the inhibitor concentration (logC (inhibitor)) is plotted on the abscissa and the corresponding Residual Activity value (Residual Activity) is plotted on the ordinate using GraphPad Prism6 software,the results are shown in FIG. two, giving the IC of the inhibitor50The value is obtained. Table 1 lists the data on the inhibition activity of Compound 1 against SARS-Cov-23 CLpro. IC (integrated circuit)50The formula is calculated as Y ═ 100/(1+10^ ((X-LogIC50))), where Y represents the residual activity fraction, X represents the common logarithm of the concentration of inhibitor compound, and Λ refers to the power algorithm. FIG. 2 is a graph showing the ratio of the concentration of various inhibitors to the activity of the inhibitory enzyme, and the inhibitory activity of the compound can be obtained as expressed by the concentration of the inhibitor at which the activity of the inhibitor is half inhibited.
Table one: tannin structures and IC's for inhibition of novel coronavirus 3C-like protease (3CLpro)50Value of
As can be seen, the above compounds have very significant inhibitory effect on the novel coronavirus 3C-like protease, IC50The value was 2.439. mu.M, indicating that tannic acid was effective in inhibiting the activity of the novel coronavirus 3C-like protease. Moreover, the coronavirus 3C-like protease is shown to have high similarity based on sequence analysis, so the compound can also effectively inhibit the activity of other coronavirus 3C-like proteases, especially SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU 1.
Furthermore, examples 1-2 (procedures and conditions identical to those of the above examples except that the inhibitors were replaced with the following compounds, respectively) were performed on the following compounds having a structure similar to that of tannic acid, and these compounds were found to have weak or no inhibition on the novel coronavirus 3C-like protease.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. Application of tannic acid (compound shown in formula 1) in preparing anti-coronavirus medicines is provided.
2. The use of claim 1, wherein said tannic acid comprises one or more of a compound having the structure of formula 1 and pharmaceutically acceptable salts thereof,
3. the use of a compound according to claim 1 or 2, wherein the tannin inhibits the enzymatic activity of the coronavirus main protease 3 Clpro.
4. The use of a compound according to claim 1 or 2, wherein the use of tannic acid is for the manufacture of a medicament for the inhibition of the coronavirus main protease 3 Clpro.
5. Use of a compound according to claim 1 or 2, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, or a novel coronavirus (SARS-CoV-2).
6. The coronavirus according to claim 5, which is preferably a novel coronavirus (SARS-CoV-2).
7. The compound of formula 1 according to claim 1 or 2, wherein the compound of formula 1 comprises one or more of optical isomers thereof, hydrates thereof; the number of crystal water of the hydrate is any real number in 1-16, and is preferably an integer.
8. A medicament for preventing and/or treating coronavirus infection or inflammation caused thereby, characterized by comprising one or more than two of tannic acid and pharmaceutically acceptable salts thereof.
9. An inhibitor drug of coronavirus main protease 3Clpro, which is characterized by comprising one or more than two of tannic acid and pharmaceutically acceptable salts thereof.
10. The medicament of claim 8 or 9, wherein the medicament is an injection, a tablet, a pill, a capsule, a suspension, a granule, a spray or an emulsion.
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| CN111759851A (en) * | 2020-08-17 | 2020-10-13 | 广东盛普生命科技有限公司 | Application of tannic acid in preparing anti-coronavirus medicine |
Non-Patent Citations (1)
| Title |
|---|
| SHAO-CHUN WANG: "Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease", 《AM J CANCER RES》 * |
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