CN110960532A - Composition of anti-coronavirus macleaya cordata benzylisoquinoline alkaloid and resveratrol and application thereof - Google Patents

Composition of anti-coronavirus macleaya cordata benzylisoquinoline alkaloid and resveratrol and application thereof Download PDF

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CN110960532A
CN110960532A CN202010107474.1A CN202010107474A CN110960532A CN 110960532 A CN110960532 A CN 110960532A CN 202010107474 A CN202010107474 A CN 202010107474A CN 110960532 A CN110960532 A CN 110960532A
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金晓飞
陈鹏
蔡媛
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Abstract

The invention discloses a bocicloram benzyl isoquinoline alkaloid and resveratrol composition for resisting coronavirus and application thereof, wherein the bocicloram benzyl isoquinoline alkaloid and resveratrol composition comprises five compositions of sanguinarine, chelerythrine, protopine, α -allocryptopine and trans-resveratrol, and the bocicloram benzyl isoquinoline alkaloid and resveratrol composition has unique binding activity on a coronavirus-related protein target spot and has obvious effect of resisting coronavirus, in particular relates to an inhibition effect on Covid-19 coronavirus, for example, the composition is expected to become a medicinal raw material for treating pneumonia caused by human infection Covid-19 coronavirus, and the composition can be used for preparing medicaments for resisting diseases caused by coronavirus infection or other products.

Description

Composition of anti-coronavirus macleaya cordata benzylisoquinoline alkaloid and resveratrol and application thereof
Technical Field
The invention relates to the field of pharmacy and medicaments for treating coronavirus infection, in particular to a composition of macleaya cordata benzyl isoquinoline alkaloid and trans-resveratrol for resisting coronavirus and application thereof.
Background
Botanical compounds, known as "seventh group nutrients," are widely found in everyday foods and are a group of non-nutritive chemicals that have special effects on human health. Related researches find that part of plant compounds have biological activity of inhibiting virus infection and are gradually one of hot spots of antiviral researches. The results of the preliminary study show that: the biological effect of the plant compound is mainly shown in the aspects of influence on the biological characteristics of a cell membrane, change of local microenvironment balance and the like, and a part of the plant compound is directly embedded into a lipid bilayer structure of the cell membrane to change the normal functional flow and potential difference of the cell membrane so as to play a certain biological effect.
Macleaya cordata (willld) r.br.) is a perennial herb, a plant of the genus Macleaya of the family papaveraceae, and stems, leaves and fruits of Macleaya cordata all contain alkaloids, the alkaloids in the Macleaya cordata plant are mainly benzylisoquinolines (benzisoquinolines) alkaloids including sanguinarine, chelerythrine, dihydrosanguinarine, dihydrochelerythrine and other benzophenanthridines (benzophenanthrines) alkaloids, protopine, allocryptopine and other protopine, etc. in the field of medicine, Macleaya cordata has strong bactericidal and bacteriostatic activity and simultaneously has good anti-inflammatory and anti-arrhythmic effects, the clinical medicinal range is wide at present, the Macleaya cordata can treat pediatric pneumonia, acute tonsillitis, kappa pneumonia, subarachnoiditis, acute appendicitis, cholecystitis, vasculitis, erosion, etc. and the like, and the clinical medicinal range is worthy of being researched by the research on the scientific inhibitory effect of inflammation of the factor for the inflammatory pathway p-356, the inflammatory pathway is a factor and the inflammatory factor B- β is capable of reducing the inflammatory factor expression of the inflammatory factor.
Resveratrol is a natural polyphenol substance with strong biological property, also called as resveratrol, and exists in a free state form under natural conditions, the chemical structure of resveratrol also exists in cis-form and trans-form isomers respectively, namely cis-resveratrol (cis-3,4 ', 5-trihydroxystilbene) and trans-resveratrol (trans-3, 4', 5-trihydroxystilbene), trans-resveratrol is a natural antioxidant existing in plants, and the trans-resveratrol plays an antioxidant role mainly through mechanisms of eliminating or inhibiting the generation of free radicals, inhibiting lipid peroxidation, regulating the activity of antioxidant-related enzymes and the like, has an inhibitory effect on staphylococcus aureus, beta-coccus, escherichia coli and pseudomonas aeruginosa, and has a strong inhibitory effect on orphan viruses, herpes simplex viruses, enteroviruses and coxsackie A, B.
Coronaviruses belong to the phylogenetic genus coronaviruses (Coronavirus), which are positive-strand RNA viruses with an envelope. Coronaviruses are becoming a research hotspot in the field of virology, due to the outbreaks of Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012. Pneumonia caused by a new variant Covid-19 coronavirus, and the characteristics of rapid virus variation, multiple hosts, stronger host adaptability and the like. As a highly pathogenic infectious virus, no effective therapeutic drug is clinically available, and the main reasons are symptomatic treatment and preventive intervention, a coronavirus is an RNA virus which is easily mutated, and the enzymatic activity of the error repair mechanism is very low during replication, so the mutation speed is very fast, and the vaccine is developed and researched according to the fixed gene or protein of the virus, so the vaccine is difficult to develop, and at present, antiviral drugs such as: saquinavir (saquinavir), indinavir (indinavir), ritonavir (ritonavir), nelfinavir (nelfinavir), amprenavir (amprenavir) and lopinavir (lopinavir) are primarily used in Human Immunodeficiency Virus (HIV) as a pathogenic retrovirus responsible for AIDS and its associated pathologies. The anti-Ebola virus test drug Reddesivir (remdesivir) developed by Gilidische scientific company can inhibit RNA synthetase (RdRp) and hopefully inhibit Covid-19 coronavirus. Therefore, there is an urgent need to find more safe and effective drugs for treating coronavirus as soon as possible.
The inventor unexpectedly discovers in a large number of scientific experiments that the composition of macleaya cordata benzylisoquinoline alkaloid and resveratrol has unique binding capacity with coronavirus related protein targets and has an inhibition effect on partial coronavirus infection, particularly on Covid-19 coronavirus.
Disclosure of Invention
Based on the above, there is a need for a macleaya cordata alkaloid and trans-resveratrol composition and application thereof, wherein the macleaya cordata alkaloid and trans-resveratrol composition has an effect of resisting coronavirus, particularly Covid-19 novel coronavirus.
The invention provides a macleaya cordata alkaloid and resveratrol composition, which comprises the following components in part by weight: the structures shown in formulas 1, 2, 3,4 and 5:
Figure DEST_PATH_IMAGE001
sanguinarine of formula 1
Figure DEST_PATH_IMAGE002
Chelerythrine of formula 2
Figure DEST_PATH_IMAGE003
Protopine of formula 3
Figure DEST_PATH_IMAGE004
Allocryptopine of formula 4
Figure DEST_PATH_IMAGE005
Trans-resveratrol trans-3, 4', 5-trihydroxystilbene of formula 5
The composition according to any of the embodiments of the first aspect of the present invention comprises more than 0.2% of the composition having the structure of formula 1-5, for example more than 0.5% of the composition having the structure of formula 1-5, for example more than 90% of the composition having the structure of formula 1-5.
A composition according to any one of the embodiments of the first aspect of the invention comprises from 10% to 90% of a composition having a structure according to formulae 1-5, for example from 90.5% to 99.8% of a composition having a structure according to formulae 1-5.
The composition according to any one of the embodiments of the first aspect of the present invention, wherein the content of the structures of formulae 6 to 17 is less than 0.2% with respect to the composition of the structures of formulae 1 to 5. For example less than 0.19%, for example less than 0.15%, for example less than 0.1%, for example less than 0.05%.
In the present invention, the phrase "content of the compound of the structure of formulae 6 to 17 for the compound of the structure of formulae 1 to 5" refers to the amount of the compound of the structure of formulae 6 to 17 relative to the compound of the structure of formulae 1 to 5 for the composition concerned. For example, if a composition contains 10mg of a composition having a structure according to formulas 1-5 and 0.02 mg of a composition having a structure according to formulas 6-17, the amount of the composition having a structure according to formulas 9-17 is 0.2% for the composition having a structure according to formulas 1-5. Similar indications for other derivatives or impurities with respect to the amounts of the compositions of formulae 1-5 are also intended.
The invention aims to provide a pharmaceutical composition which has obvious inhibiting or blocking effect on coronavirus, particularly Covid-19 coronavirus, such as raw materials of compounds with stable pharmaceutical characteristics, particularly formulas 1-5 or preparations prepared from the raw materials. And by controlling the derivatives or impurities in the raw materials of the compounds of formulae 1 to 5, formulae 6 to 17 to be below a certain range, excellent stability of the pharmaceutical combination preparation is achieved.
According to the invention, through setting up positive control and carrying out artificial intelligent simulation drug molecule target screening, the macleaya cordata benzylisoquinoline alkaloid and trans-resveratrol composition has good binding activity and obvious virus activity inhibition effect on a coronavirus characteristic protein target taking Covid-19 coronavirus as an example, so that the composition is expected to be used as a potential drug for treating main infection of coronavirus taking Covid-19 coronavirus as an example.
In one embodiment of the invention, the composition for inhibiting viral infection is specifically composed of sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol; the mass ratio of sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol is 1:0.1:0.1:0.1: 1.
In the present invention, the inhibition of coronavirus infection is (a) or (b) as follows:
(a) preventing coronavirus infection;
(b) inhibiting infection of a host or a host cell by a coronavirus when the coronavirus and the coronavirus act simultaneously on the host or the host cell.
More specifically, in the examples of the present invention, the inhibitory effect of the agent on the coronavirus infection is embodied as follows: the composition is administered simultaneously with or prior to coronavirus infection of the cells, and the half inhibitory concentration of the composition against coronavirus is significantly reduced compared to a positive control drug that inhibits viral infection. The positive control drug is Ribavirin (Ribavirin).
The invention takes Covid-19 coronavirus (MHV) as an experimental object, adopts an artificial intelligent computer-aided drug molecular structure design system, and respectively tests the combination rule and characteristics of five plant compound monomers, namely sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol, and coronavirus protein targets. The results confirmed that: compared with the potential positive control medicament of the Reidesvir, the five plant compound monomers provided by the invention have obvious virus target binding activity, and show that the five plant compound monomers can effectively inhibit infection of coronavirus.
The invention takes coronavirus (MHV) as an experimental object, adopts a method for observing cytopathic effect, and respectively analyzes rules and characteristics of five plant compound monomers of sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol and mixed preparations thereof for inhibiting virus infection under different infection conditions. The results confirmed that: the cytotoxicity of the five plant compound monomers and the compound formula composition provided by the invention is not higher than that of ribavirin which is a control sample obtained with safety permission, and the five plant compound monomers and the compound formula composition are safer. Under the safe use concentration, the compound formula composition of sanguinarine, chelerythrine, protopine, allocryptopine, resveratrol monomer and plant extract is used preventively, so that the infection of coronavirus can be effectively inhibited. The compositions provided by the present invention have commercial value for further development as inhibitors of coronavirus infection.
The invention provides a composition for preventing or treating coronavirus infection, which comprises the active ingredients of macleaya cordata benzylisoquinoline alkaloid and trans-resveratrol, and comprises the macleaya cordata benzylisoquinoline alkaloid, the trans-resveratrol and one or more pharmaceutically acceptable carriers. The carrier comprises a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant and a synergist which are conventional in the pharmaceutical field. The medicine can be made into injection, tablet, pill, capsule, suppository, suspension or emulsion. The administration route can be oral, percutaneous, intravenous or intramuscular injection, and mucosal administration.
The invention has the advantages and positive effects that: the invention provides an inhibitor for coronavirus infection exemplified by Covid-19 coronavirus, which is a composition of macleaya cordata benzylisoquinoline alkaloid and trans-resveratrol, and has a remarkable inhibitory effect on the coronavirus activity exemplified by Covid-19 coronavirus.
Description of the figures
FIG. 1 shows the docking pattern of sanguinarine molecules, Reidsievir molecules and Covid-19 coronavirus RNA synthetase RdRp.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the specific embodiments of the present invention and the accompanying drawings, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
The quantitative experimental data referred to in the following examples are expressed as means ± standard deviation (± s), and the statistical processing of comparative data between groups was performed using the SPSS 17.0 statistical software using the one-way horizontal analysis of variance method.
① as a culture solution of a virus coronavirus (mouse hepatitis coronavirus A59 strain, MHV-A59 for short), 0.2mg/ml glutamine, 100U/ml penicillin, streptomycin ② as a cell growth culture solution, 2 percent of fetal bovine serum, ③ as the rest, 1 as well as 1 as a virus proliferation culture solution, which are the same as the cell growth culture solution.
And (3) testing the sample: sanguinarine CAS #: 5578-73-4, chelerythrine CAS #: 34316-15-9, protopine CAS #:130-86-9, allocryptopine CAS #: 485-91-6 and resveratrol CAS #: 501-36-0
Positive control: ribavirin (Ribavirin)
The instrument equipment comprises: an inverted phase contrast microscope, a multifunctional cell culture box and a multifunctional microplate reader.
The test process comprises the following steps: 1. cell recovery and passage → 2, virus propagation → 3, and virus titer TCID50 assay.
The first embodiment,
Preparation of macleaya cordata benzyl isoquinoline alkaloid and resveratrol composition virus infection inhibitor
Uniformly mixing sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol according to the mass ratio of 1:0.1:0.1:0.1:1 to obtain a composition formula preparation.
Dissolving in PBS buffer solution before experiment, making into 2800 μ g/ml (total concentration of sanguinarine, chelerythrine, protopine, allocryptopine and resveratrol in solution), filtering, sterilizing, and storing at-20 deg.C.
Example II,
Cytotoxicity assays
This example uses neutrophilic erythrophagocytosis to determine the cytotoxicity of the formulation of the composition prepared in the first example on mammalian cells.
TABLE 1 results of the maximum cell nontoxicity test of the formulations of the phytochemical monomers and compositions
Figure DEST_PATH_IMAGE006
EXAMPLE III coronavirus infection inhibition assay
This example uses the CPE method to determine the inhibitory effect of the formulation of the composition prepared in example 1 on coronavirus infection. The coronavirus to be tested was murine hepatitis coronavirus A59 strain.
The results show that both the composite formulation and ribavirin interfered with coronavirus infection of 17Cl-1 cells. Wherein, under the condition that the inhibitor is added at the same time of virus adsorption and before adsorption, the composite formulation preparation of the composition has the best effect of inhibiting virus infection, the half inhibitory concentration of the virus is respectively 168 +/-11 mu g/ml and 129 +/-16 mu g/ml, and under the condition that the inhibitor is added after virus adsorption, the control drug ribavirin has better effect of inhibiting virus, and the half inhibitory concentration of the virus is 243 +/-25 mu g/ml. Among the monomeric inhibitors, sanguinarine is most effective in inhibiting virus infection when added before virus adsorption, and has a half inhibitory concentration of 162 + -14 μ g/ml, and chelerythrine, protopine, allocryptopine and resveratrol are added after virus adsorption, and can effectively inhibit coronavirus infection. Specific results are shown in Table 2
TABLE 2 half inhibitory concentration of each inhibitor against coronavirus infection (IC 50)
Figure DEST_PATH_IMAGE007
The experimental results of the combined examples 2 and 3 show that: the cytotoxicity of the formulation of the composition provided by the invention is not higher than that of ribavirin of a control sample which has obtained safety permission, and the formulation is safer. Under the safe use concentration, the compound formula preparation of the composition provided by the invention can be used prophylactically, and the infection of coronavirus can be effectively inhibited. The compound formula preparation provided by the invention has commercial value for further developing a novel coronavirus infection inhibitor.
Example four Artificial Intelligent simulated drug molecule Covid-19 coronavirus protein target virtual screening assay
The target drug molecules for the virtual screening assay include: clinical commonly used medicines of ritonavir, lopinavir, montelukast, xinafillin, remixivir, 6 polydatin and 7 plant compounds such as sanguinarine, resveratrol and the like.
Molecular docking simulation was performed using the receptor grid prepared by the Glide program of schrodinger and the opls3 force field in the homology simulation complex with a lateral length of 20 Å, the grid center was set to the centroid of the ligand, the ligand docked in SP (standard precision) mode, and all other parameters were set as defaults for the Glide docking process.
Specific results are shown in Table 3
TABLE 3 three Covid-19 target protein entities of interest, binding Glide docking score and MMGBSA free energy calculation.
Figure DEST_PATH_IMAGE008
The virtual screening experiment result shows that: the composition of benzylisoquinoline alkaloids and resveratrol provided by the invention has obvious binding activity on three Covid-19 target protein entities, wherein Sanguinarine Sanguinarine has the most outstanding performance, and compared with a common positive control drug molecule Redcisvir Remdesivir, the Sanguinarine Sanguinarine and Covid-19 coronavirus RNA synthetase (RdRp) have obviously lower free energy required for binding, which suggests that the Sanguinarine Sanguinarine may have more outstanding performance on inhibition of the virus RNA synthetase (RdRp).
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (8)

1. The composition of macleaya cordata benzylisoquinoline alkaloid and trans-resveratrol is characterized in that the composition consists of components with structures shown in the following formulas 1, 2, 3,4 and 5:
Figure 912090DEST_PATH_IMAGE001
sanguinarine of formula 1
Figure 485023DEST_PATH_IMAGE002
Chelerythrine of formula 2
Figure 451711DEST_PATH_IMAGE003
Protopine of formula 3
Figure 253445DEST_PATH_IMAGE004
Allocryptopine of formula 4
Figure 989189DEST_PATH_IMAGE005
Trans-resveratrol trans-3, 4', 5-trihydroxystilbene of formula 5.
2. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 1, wherein the composition contains the following compounds with the structures of 6-17 in the presence of derivatives or impurities which may be generated in the preparation process:
Figure 1531DEST_PATH_IMAGE006
formula 6 Chelilutine methoxyl chelerythrine
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Chelirubine chelidonine of formula 7
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Bocconine macleaya cordata alkali of formula 8
Figure 120032DEST_PATH_IMAGE009
9 Dihydrosanguina Dihydrosanguinarine
Figure 785500DEST_PATH_IMAGE010
Dihydrochelerythrine of the formula 10 Dihydrochelerythrine
Figure 726780DEST_PATH_IMAGE011
Formula 11 Oxysangunarine oxosanguinarine
Figure 122514DEST_PATH_IMAGE012
Formula 12N-norsanguinarine desmethylsanguinarine
Figure 583582DEST_PATH_IMAGE013
Formula 13(s) -Scoulerine golden violaxolide
Figure 934798DEST_PATH_IMAGE014
Formula 14 Creaminess violaxanthin
Figure 848527DEST_PATH_IMAGE015
Coptisine of formula 15
Figure 45022DEST_PATH_IMAGE016
The formula 16 Berberine Berberine
Figure 609864DEST_PATH_IMAGE017
Formula 17 Dehydrocephaloline dehydrocorynoline.
3. The composition of macleaya cordata benzylisoquinoline alkaloid and trans-resveratrol according to claim 1, wherein the composition is a raw material or a drug prepared from the raw material with the compound of formula 1-5 as an active ingredient, and the method comprises the steps of enabling the mass fraction of sanguinarine in the composition to be 0.2% -98%, the mass fraction of chelerythrine to be 0.2% -98%, the mass fraction of raw opium to be 0.2% -98%, the mass fraction of allocryptopine to be 0.2% -98%, and the mass fraction of trans-resveratrol to be 0.2% -98%.
4. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 2, wherein the derivatives or impurities of the compounds of formulae 6-17 are controlled within a range, and the total content of the compounds of formulae 6-17 relative to the compounds of formulae 1-5 is less than 0.2% so that the composition exhibits low growth of the derivatives or impurities of the compounds of formulae 6-17 during long-term storage.
5. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 1, wherein the composition is used in the preparation of a medicament for the treatment of coronavirus infection.
6. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 1, wherein the composition is used for preparing a medicament for treating Covid-19 coronavirus infection.
7. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 1, wherein the composition is in combination with one or more pharmaceutically acceptable carriers; the carrier comprises a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant and a synergist which are conventional in the pharmaceutical field.
8. The composition of macleaya cordata benzylisoquinoline alkaloids and trans-resveratrol according to claim 1, wherein the composition is characterized by containing an injection, tablet, pill, capsule, suppository, suspension or emulsion of the composition.
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CN111803472A (en) * 2020-07-03 2020-10-23 深圳市第三人民医院 A kind of anti-novel coronavirus drug and its application
WO2021207271A1 (en) * 2020-04-10 2021-10-14 Ebvia Inc. Organoselenide glutathione peroxidase mimetics for the treatment of inflammatory pulmonary disorders
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WO2021207271A1 (en) * 2020-04-10 2021-10-14 Ebvia Inc. Organoselenide glutathione peroxidase mimetics for the treatment of inflammatory pulmonary disorders
WO2021204520A1 (en) * 2020-04-10 2021-10-14 Galenus G.H. Ag Composition comprising resveratrol
WO2021235392A1 (en) * 2020-05-18 2021-11-25 オンコリスバイオファーマ株式会社 Anti-sars-cov-2 durg
JP7765835B2 (en) 2020-05-18 2025-11-07 オンコリスバイオファーマ株式会社 Anti-SARS-CoV-2 drug
JPWO2021235392A1 (en) * 2020-05-18 2021-11-25
WO2021245700A3 (en) * 2020-06-03 2022-01-13 Jubilant Generics Limited Pharmaceutical lipid compositions of remdesivir
CN111518158A (en) * 2020-06-16 2020-08-11 北京赫尔默技术有限公司 Compound for resisting hand-foot-and-mouth disease and preparation method and application thereof
CN111803472A (en) * 2020-07-03 2020-10-23 深圳市第三人民医院 A kind of anti-novel coronavirus drug and its application
WO2022015570A1 (en) * 2020-07-11 2022-01-20 The Regents Of The University Of California Compositions and methods for inhibiting and treating coronavirus infections
CN114641285A (en) * 2020-09-28 2022-06-17 爱贝施生物技术研究有限公司 Formulations comprising plant extracts
US20220257614A1 (en) * 2021-02-16 2022-08-18 New York Medical College Use of 12-lipoxygenase inhibitors in the treatment of covid-19
CN117957009A (en) * 2021-06-07 2024-04-30 段美南 Methods and compositions for preventing and treating severe specific infectious pneumonia (COVID-19) and long-term severe specific infectious pneumonia (LONG COVID)
WO2024088403A1 (en) * 2022-10-27 2024-05-02 北京化工大学 Use of isoquinoline alkaloid in prevention and treatment of diseases caused by coronaviral infections

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