CN113827586B - Application of nortriptyline hydrochloride in preparation of anti-enterovirus drugs - Google Patents

Application of nortriptyline hydrochloride in preparation of anti-enterovirus drugs Download PDF

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CN113827586B
CN113827586B CN202111038257.2A CN202111038257A CN113827586B CN 113827586 B CN113827586 B CN 113827586B CN 202111038257 A CN202111038257 A CN 202111038257A CN 113827586 B CN113827586 B CN 113827586B
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nortriptyline hydrochloride
enterovirus
nortriptyline
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CN113827586A (en
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杨庆雨
张定宇
黄朝林
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Wuhan Jinyintan Hospital Wuhan Infectious Disease Hospital
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Abstract

The invention provides an application of nortriptyline hydrochloride in preparation of anti-enterovirus drugs, which proves that nortriptyline hydrochloride has stronger antiviral activity on enteroviruses such as EV71, Coxsackie virus and the like, can obviously inhibit cytopathic effect (CPE) generated by the enteroviruses on a host cell RD, and enhances the cell survival rate; can inhibit the replication of viruses and show stronger antiviral effect at the cellular level, and has obvious technical effect. The results of the invention show that the compound nortriptyline hydrochloride has the potential to prepare the specific treatment medicine for resisting the enterovirus infection, and has better clinical application prospect.

Description

Application of nortriptyline hydrochloride in preparation of anti-enterovirus drugs
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of nortriptyline hydrochloride in preparation of an anti-enterovirus medicine.
Background
Enterovirus 71 (Enterovirus, EV71) is a member of the Enterovirus genus of the Picornaviridae family (Picornaviridae) and is a non-enveloped virus, and virions are in the form of regular icosahedral spheroids with a diameter of about 30nm, and have genomes of single positive RNA strands and a length of about 7.5kb, and are one of the most major pathogens causing infantile hand-foot-and-mouth disease. Infants with hand-foot-and-mouth are sometimes accompanied by serious central nervous system complications, including aseptic meningitis, encephalitis, poliomyelitis-like paralysis, neurological cardiopulmonary failure, and the like, and even death. Humans are the only natural hosts of enteroviruses, and spread by intimate contact between humans (through fingers, tableware and food). The infected person has viruses in the pharynx and the intestine, and the time for expelling the viruses from the feces is long and can last for several weeks. Fecal-oral is the primary route of transmission. Occasionally, it can also be spread by droplets. The majority occurs in children under 5 years old, with the highest incidence among children 1-2 years old.
Enterovirus 71 ((Enterovirus, EV71) belongs to a member of Enterovirus (Enterovirus) of the family Picornaviridae (Picornaviridae), is one of the most major pathogens causing infantile hand-foot-and-mouth diseases, sometimes with serious central nervous system complications, including aseptic meningitis, brainstem encephalitis, autonomic nervous disorders, pulmonary edema, and the like, and even leading to death. since the first report in 1969, EV71 infectious diseases have been outbreaks and epidemics worldwide, and are severe in Asia Pacific areas, particularly China at present, prevention and treatment of viral diseases mainly depend on vaccines and drugs, related vaccines are marketed in 2015, no specific data exist at present to support marketed vaccines to protect enteroviruses of other serotypes, treatment methods against EV71 virus infection are quite limited, and main treatment methods are symptomatic support treatment and broad-spectrum antiviral treatment, it has limited curative effect, large individual difference and difficult popularization. Therefore, the research and development of related antiviral drugs can be a key direction for overcoming the virus, and the development of specific and effective anti-EV 71 drugs is imperative.
Therefore, there is a need to develop a new enterovirus infectious disease drug.
Disclosure of Invention
The invention aims to provide application of nortriptyline hydrochloride in preparation of an anti-enterovirus medicament, which finds that nortriptyline hydrochloride has a strong inhibiting effect on enteroviruses for the first time and provides a direction for treating and preventing enterovirus infectious diseases.
In order to realize the purpose, the invention adopts the following technical scheme:
the invention provides an application of nortriptyline hydrochloride in preparing an anti-enterovirus medicament.
Further, the enterovirus includes at least one of enterovirus type 71, coxsackievirus type B3 and coxsackievirus type B4.
Further, the pharmaceutically acceptable derivative of nortriptyline hydrochloride comprises: nortriptyline ditosylate hydrochloride, nortriptyline tosylate hydrochloride, pharmaceutically acceptable salts of nortriptyline hydrochloride, and pharmaceutically acceptable acid addition salts of nortriptyline hydrochloride.
Further, in the pharmaceutically acceptable acid addition salt of nortriptyline hydrochloride, the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, and camphoric acid.
Further, the pharmaceutically acceptable salt of nortriptyline hydrochloride includes at least one of an inorganic salt and an organic salt.
Further, the inorganic salt comprises one of hydrochloride, hydrobromide, sulfate, nitrate and phosphate; the organic salt comprises one of mesylate, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, benzene sulfonate, benzoate, benzene sulfonate, lactate and malate. The embodiment of the invention specifically selects nortriptyline hydrochloride.
Furthermore, the anti-enterovirus medicine also comprises pharmaceutically acceptable auxiliary materials and carriers.
Further, the adjuvant includes at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a colorant.
Further, the dosage form of the anti-enterovirus medicament comprises at least one of granules, tablets, pills, capsules, injections or dispersing agents.
Further, the anti-viral means of the anti-enterovirus drug comprises: inhibit enterovirus intracellular nucleic acid replication, viral protein expression and infection.
One or more technical solutions in the embodiments of the present invention at least have the following technical effects or advantages:
the invention provides an application of nortriptyline hydrochloride in preparing an anti-enterovirus medicament, wherein the nortriptyline hydrochloride is used as a tricyclic antidepressant for short-term treatment of various forms of depression. Test results show that nortriptyline hydrochloride has stronger antiviral activity on enteroviruses such as EV71, CVB3, CVB4 and the like, can remarkably inhibit cytopathic effect (CPE) of the enteroviruses on host cells RD, and enhances the cell survival rate; can inhibit replication of enterovirus, shows strong antiviral effect at cell level, and has obvious technical effect. The results of the invention show that the compound nortriptyline hydrochloride has the potential to prepare the specific treatment medicine for resisting the enterovirus infection, and has better clinical application prospect.
Meanwhile, the nortriptyline hydrochloride micromolecule compound has a simple synthesis process and is easy to produce and popularize on a large scale; the antiviral activity of nortriptyline hydrochloride is not reported, and the nortriptyline hydrochloride has a certain guiding effect on the development of the anti-enterovirus activity; the anti-enterovirus medicine is searched from the compounds with similar structures, the action target of the anti-enterovirus medicine is easy to be found through the structure-activity relationship research, and certain reference significance is provided for further medicine development.
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In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the description below are some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.
FIG. 1 is a chart showing the results of RD cytotoxicity assay of nortriptyline hydrochloride against EV71 virus in example 1 of the present invention;
FIG. 2 is a graph showing the effect of nortriptyline hydrochloride on the cytopathic effect (CPE) of EV71 virus in host RD cells in example 2;
FIG. 3 is a graph showing the analysis of the results of the detection of the expression of the antiviral activity of nortriptyline hydrochloride of different concentrations in example 3 of the present invention;
FIG. 4 is a diagram showing the analysis of the detection results of the influence of nortriptyline hydrochloride on the proliferation of EV71 virus in example 4 of the present invention;
FIG. 5 is a graph of calculated median inhibitory concentrations of drugs against viral replication in example 4 of the present invention;
FIG. 6 is a graph showing the analysis of the results of detecting the gene expression of the EV71 virus inhibited by nortriptyline hydrochloride by immunofluorescence in example 5 of the present invention;
FIG. 7 is a graph showing the results of the effect of nortriptyline hydrochloride on replication of CVB3 and CVB4 in example 6 of the present invention, wherein FIG. 7A is the effect of nortriptyline hydrochloride on replication of CVB3 and FIG. 7B is the effect of nortriptyline hydrochloride on replication of CVB 4.
Detailed Description
The present invention will be specifically explained below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly presented thereby. It will be understood by those skilled in the art that these specific embodiments and examples are illustrative of the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be obtained by an existing method.
In order to solve the technical problems, the general idea of the embodiment of the application is as follows:
nortriptyline hydrochloride is a dibenzocycloheptadiene tricyclic antidepressant, is a metabolite of amitriptyline, has an antidepressant effect, and is suitable for patients with depression accompanied by stress and anxiety. The chemical structural formula of nortriptyline hydrochloride is as follows:
Figure GDA0003586835260000041
the inventor of the application combines the virus RNA level analysis, the titer determination and the MTT determination cell survival rate detection method to perform the anti-enterovirus activity research experiment on the nortriptyline hydrochloride small molecular compound, and the data analysis in the embodiment adopts Graphpad software to perform statistical analysis, so that the nortriptyline hydrochloride is found to have a strong inhibition effect on enteroviruses. The enterovirus includes at least one of enterovirus 71, coxsackievirus B3 and coxsackievirus B4.
Specifically, the method comprises the following steps: nortriptyline hydrochloride was evaluated for inhibitory activity against EV71 virus and tested for activity by standard antiviral activity test methods. Through a large number of biological experiments, nortriptyline hydrochloride is found to have better activity of inhibiting EV71 replication, and specifically shows that the nortriptyline hydrochloride can inhibit intracellular nucleic acid replication and virus protein expression of EV71 virus, so that the proliferation of the virus is inhibited.
The experimental result shows that the nortriptyline hydrochloride has stronger antiviral activity on EV71, can obviously inhibit cytopathic effect (CPE) generated by the EV71 virus on a host cell RD, and enhances the cell survival rate; can inhibit the replication of viruses and show stronger antiviral effect at the cellular level, and has obvious technical effect.
In addition, under the condition of different concentrations of nortriptyline hydrochloride, the nortriptyline hydrochloride has obvious inhibition effect on the replication of CVB3 and CVB 4.
In conclusion, the results of the invention show that the compound nortriptyline hydrochloride has the potential to prepare the specific therapeutic drug for resisting EV71 infection, and has better clinical application prospect.
Therefore, the invention provides an application of nortriptyline hydrochloride in preparing anti-enterovirus medicines, wherein the application refers to that the nortriptyline hydrochloride is added with pharmaceutically acceptable auxiliary materials and carriers to prepare an anti-EV 71 virus preparation, the auxiliary materials comprise at least one of a filling agent, a disintegrating agent, a binding agent, an excipient, a diluent, a lubricant, a sweetening agent or a coloring agent, and different auxiliary materials are selected according to the requirements of pharmaceutical dosage forms. The preparation is granule, tablet, pill, capsule, injection or dispersant.
It can be understood that the invention also belongs to the protection scope of the invention when the nortriptyline hydrochloride is used as a lead compound for further structure optimization and is used for preparing the medicine for treating the enterovirus infectious diseases. Wherein the pharmaceutical derivative of nortriptyline hydrochloride comprises: pharmaceutically acceptable salts of nortriptyline hydrochloride, pharmaceutically acceptable acid addition salts of nortriptyline hydrochloride.
The use of nortriptyline hydrochloride in the preparation of anti-enterovirus drugs according to the present application will be described in detail below with reference to examples and experimental data.
Example 1 cytotoxicity assay of nortriptyline hydrochloride
In RD cells, p-hydrochloric acidThe cytotoxicity of nortriptyline was examined. RD cells were seeded in 96-well plates at 37 ℃ with 5% CO 2 After culturing for 12-16h in an incubator, discarding the cell culture solution, adding cell maintenance solutions containing nortriptyline hydrochloride with different concentrations for testing, continuously culturing, 3 multiple wells for each group, and adding the same amount of nortriptyline hydrochloride-free cell maintenance solution to a control group. After 48h of action, staining with MTT and detecting OD 492 nM, cell viability was analyzed.
And (4) analyzing results: as shown in FIG. 1, Graphpad Prism8 software calculates half toxic concentration (CC 50) of drug on cells and CC of nortriptyline hydrochloride 50 It was 7183 nM. In subsequent examples, nortriptyline hydrochloride was used at a maximum concentration of 5000nM, which is within the safe and non-toxic range.
Example 2 detection of the antiviral Activity of nortriptyline hydrochloride on EV71
RD cells were plated in 96-well cell culture plates at 37 ℃ with 5% CO 2 After the culture in an incubator for 12-16h, 100TCID 50 The EV71 virus liquid infects cells for 2h, cell maintenance liquid containing nortriptyline hydrochloride with different concentrations is respectively added for continuous culture for about 48h, and the negative control is added with the cell maintenance liquid without nortriptyline hydrochloride with the same volume. When the virus control wells showed CPE lesions in about 90%, cytopathic effect (CPE) was observed under a microscope.
And (4) analyzing results: the RD cell CPE effect caused by inhibition of EV71 by nortriptyline hydrochloride is shown in figure 2, RD cells infected by EV71 become round and are separated from cell plate walls, and treatment of experimental compounds with different concentrations has a remarkable inhibition effect on the pathological effect.
Example 3 detection of inhibition of EV71 proliferation Activity by nortriptyline hydrochloride
Inoculating RD cells into 24-well cell culture plate, culturing at 37 deg.C in 5% CO2 incubator for 12-16 hr, and culturing with 100TCID 50 After 2h of infection with the EV71 virus solution, the cells were treated with cell maintenance solutions containing different concentrations of the experimental nortriptyline hydrochloride, and the same volume of the cell maintenance solution without nortriptyline hydrochloride was added to the negative control. After 24h of treatment, the effect of inhibiting virus proliferation was examined by TCID50 titer assay.
And (4) analyzing results: the detection result is shown in fig. 3, under different concentration conditions, the compound nortriptyline hydrochloride has a remarkable inhibition effect on EV71, and the drug treatment group can obviously reduce the value of TCID50 of the virus compared with a control group. At the nortriptyline hydrochloride concentration of 20 μ M, the inhibition rate on EV71 virus was 83%.
Example 4 Effect of nortriptyline hydrochloride on EV71 replication
The experiment detects that nortriptyline hydrochloride has better inhibitory activity to EV 71:
RD cells were seeded in 12-well cell culture plates at 37 ℃ with 5% CO 2 After 12-16h of incubation in an incubator and 2h of infection with 100TCID50 of EV71 virus, treatment was carried out with test compounds (nortriptyline hydrochloride) containing different concentrations, and the negative control was supplemented with the same volume of cell maintenance medium without nortriptyline hydrochloride. After 16h of treatment, collecting the cultured cells to extract total RNA, and detecting the effect of nortriptyline hydrochloride on inhibiting virus replication by a real-time fluorescent quantitative PCR (qPCR) method.
And (4) analyzing results: the detection result is shown in fig. 4, the Graphpad Prism8 software analyzes the expression level and half inhibitory Concentration (IC 50) of the VP1 gene of the virus, fig. 4 shows the effect of nortriptyline hydrochloride on the expression of the EV71VP1 gene, nortriptyline hydrochloride has a significant inhibitory effect on the expression of the VP1 gene of the EV71 virus under different Concentration conditions, fig. 5 shows the calculation of the half inhibitory Concentration (Concentration for 50% of maxiinhibitory, IC50) of the drug on virus replication, and IC50 of nortriptyline hydrochloride is 66.64 nM.
Example 5 detection of Effect of nortriptyline hydrochloride on inhibition of EV71 Virus Gene expression by immunofluorescence
The experiment detects that nortriptyline hydrochloride has better inhibitory activity to EV71 replication:
RD cells were seeded in 24-well cell culture plates at 37 ℃ with 5% CO 2 Culturing in incubator for 12-16h, infecting with EV71 virus solution of 100TCID50 for 2h, treating with test compound (nortriptyline hydrochloride) containing different concentrations, and adding different medicinal substances into negative controlA maintenance solution for the substance. After 16h of treatment, 4% formaldehyde was added to fix the cells, and after incubation overnight at 4 ℃ with the addition of an antibody against dsRNA, analysis and photography were performed by a high content instrument.
And (4) analyzing results: as a result, as shown in fig. 6, the antibody labeled with the red fluorescent dye specifically binds to the RNA of the virus, and the red fluorescence is proportional to the number of viruses, and the result shows that the number of red fluorescence gradually decreases with the increase in the drug concentration, and the growth of the virus is inhibited by the process concentration.
Example 6 Effect of nortriptyline hydrochloride on replication of CVB3 and CVB4
Hela cells were seeded in 12-well plate cell culture plates at 37 ℃ in 5% CO 2 Culturing in incubator for 12-16h, and culturing with 100TCID 50 After 2h infection with CVB3 and CVB4, respectively, the virus solutions were treated with test compounds (nortriptyline hydrochloride) containing different concentrations, and the negative control was supplemented with the same volume of cell maintenance solution without nortriptyline hydrochloride. After 17h of treatment, the effect of nortriptyline hydrochloride on inhibiting virus replication is detected by a real-time fluorescent quantitative PCR (qPCR) method.
And (4) analyzing results: the detection result is shown in fig. 7, wherein fig. 7A shows the influence of nortriptyline hydrochloride on the replication of CVB3, fig. 7B shows the influence of nortriptyline hydrochloride on the replication of CVB4, and nortriptyline hydrochloride has a significant inhibition effect on the replication of CVB3 and CVB4 under different concentration conditions.
In conclusion, the nortriptyline hydrochloride has remarkable activity of inhibiting EV71 replication, wherein the nortriptyline hydrochloride has the best inhibition effect, can strongly inhibit RD cytopathic effect caused by EV71 virus, and enhances the cell survival rate; inhibiting the replication of the level of viral RNA, and has the potential to further develop and prepare a medicament which is clinically effective against the EV71 virus infection.
Finally, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including the preferred embodiment and all changes and modifications that fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (5)

1. Use of nortriptyline hydrochloride in the manufacture of a medicament for combating enteroviruses, said enteroviruses comprising at least one of enterovirus type 71, coxsackievirus type B3 and coxsackievirus type B4.
2. The use of claim 1, wherein the anti-enterovirus medicament further comprises pharmaceutically acceptable excipients and carriers.
3. The use according to claim 2, wherein the adjuvant comprises at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a coloring agent.
4. The use of claim 1, wherein the dosage form of the anti-enterovirus drug comprises at least one of granules, tablets, pills, capsules, injections or dispersions.
5. The use according to claim 1, wherein the anti-viral means of the anti-enteroviral drug comprises: inhibit enterovirus intracellular nucleic acid replication, viral protein expression and infection.
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