CN113827596B - Application of lapatinib and/or pharmaceutically acceptable derivatives thereof in preparation of anti-enterovirus drugs - Google Patents
Application of lapatinib and/or pharmaceutically acceptable derivatives thereof in preparation of anti-enterovirus drugs Download PDFInfo
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- CN113827596B CN113827596B CN202111038267.6A CN202111038267A CN113827596B CN 113827596 B CN113827596 B CN 113827596B CN 202111038267 A CN202111038267 A CN 202111038267A CN 113827596 B CN113827596 B CN 113827596B
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Abstract
The invention provides application of lapatinib and/or pharmaceutically acceptable derivatives thereof in preparation of anti-enterovirus drugs, and the application proves that lapatinib has stronger antiviral activity on enteroviruses such as EV71, Coxsackie virus and the like, can remarkably inhibit cytopathic effect (CPE) generated by the enteroviruses on host cells RD, and enhances cell survival rate; can inhibit replication of enterovirus, has strong antiviral effect at cell level, and has obvious technical effect. The result of the invention shows that the compound lapatinib has potential to prepare specific treatment medicines for resisting enterovirus infection, and has better clinical application prospect.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of lapatinib and/or pharmaceutically acceptable derivatives thereof in preparation of an anti-enterovirus medicament.
Background
Enterovirus 71 (Enterovirus, EV71) is a member of the genus Enterovirus of the family Picornaviridae (Picornaviridae) and is a non-enveloped virus, the virion is in the shape of a regular icosahedral sphere with a diameter of about 30nm, the genome of the virion is a single positive RNA strand, the length of the virion is about 7.5kb, and the virion is one of the most main pathogens causing hand-foot-and-mouth disease of infants. The children with hand-foot-mouth disease are sometimes accompanied with serious central nervous system complications, including aseptic meningitis, encephalitis, poliomyelitis-like paralysis, neurogenic 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 presence of virus in the throat and bowel of the infected person with increased time to viral ejection from the stool could be maintained for weeks. Fecal-oral is the primary route of transmission. Occasionally, it may be transmitted by droplets. The disease is most frequently found in children under 5 years old, and the incidence rate is highest in children under 1-2 years old.
Enterovirus 71 ((Enterovirus, EV 71)) belongs to a member of Enterovirus (Enterovirus) of Picornaviridae (Picornaviridae), is one of the most main pathogens causing infantile hand-foot-and-mouth diseases, sometimes is accompanied by serious central nervous system complications including aseptic meningitis, brainstem encephalitis, autonomic nervous disorders, pulmonary edema and the like, and even causes death. since the first report in 1969, EV71 infectious diseases have been frequently outbreaks and epidemics worldwide, and are severe in Asia-Pacific regions, particularly China at present, viral disease prevention and treatment mainly depend on vaccines and medicaments, related vaccines are marketed in 2015, no specific data can support marketed vaccines to protect enteroviruses of other serotypes at present, treatment methods for EV71 virus infection are quite limited, and main treatment methods are symptomatic support treatment and broad-spectrum antiviral therapy, it has limited curative effect, large individual difference and difficult popularization. Therefore, the development of related antiviral drugs is 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 application finds that the lapatinib has a strong inhibiting effect on enteroviruses and provides a direction for treating and preventing enterovirus infectious diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides application of lapatinib and/or pharmaceutically acceptable derivatives thereof in preparation of 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 lapatinib comprises: lapatinib ditosylate, lapatinib tosylate, pharmaceutically acceptable salts of lapatinib, pharmaceutically acceptable acid addition salts of lapatinib.
Further, in the pharmaceutically acceptable acid addition salt of lapatinib, 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 lapatinib 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 can specifically select the hydrochloride of lapatinib.
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 lapatinib and/or the medicinal derivative thereof provided by the invention are applied to preparation of an anti-enterovirus medicament, and lapatinib is always used as a compound for targeted treatment of breast cancer, so that a new application of lapatinib in resisting enterovirus is discovered for the first time. The experimental result shows that lapatinib has strong antiviral activity on enteroviruses such as EV71 and CVB3, can remarkably inhibit cytopathic effect (CPE) generated by EV71 viruses on host cells 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 result of the invention shows that the compound lapatinib has potential to prepare specific treatment medicines for resisting enterovirus infection, and has better clinical application prospect.
Meanwhile, the lapatinib micromolecule compound disclosed by the invention is simple in synthesis process and easy to produce and popularize on a large scale; the antiviral activity of lapatinib is not reported, and the lapatinib has a certain guiding effect on 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.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description 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 graph showing the analysis of the RD cytotoxicity test results of Lapatinib on the action of EV71 virus in example 1 of the present invention;
FIG. 2 is a graph showing the effect of lapatinib on cytopathic effect (CPE) produced by EV71 virus in host RD cells in example 2 of the present invention;
FIG. 3 is a graph showing the analysis of the antiviral activity test results of lapatinib at different concentrations in example 3 of the present invention;
FIG. 4 is a graph showing the analysis of the detection results of the influence of lapatinib on the proliferation of EV71 virus in example 4 of the present invention;
FIG. 5 is a graph showing the analysis of the test results of the influence of lapatinib on EV71 replication in example 5 of the present invention;
FIG. 6 is a graph showing the analysis of the detection results of the influence of lapatinib on the replication of CVB3 and CVB4 viruses in example 6 of the present invention; wherein, fig. 6A is the effect of lapatinib on CVB3 replication and fig. 6B is the effect of lapatinib on CVB4 replication.
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 for the purpose of illustrating 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:
lapatinib (Lapatinib ditosylate) is N- (3-chloro-4- ((3-fluorophenyl) methoxy) phenyl) -6- (5- (((2- (methylsulfonyl) ethyl) amino) methyl) -2-furyl) -4-quinazolinamine di-p-toluenesulfonate, a new breast cancer targeted therapy medicament developed by Kulanin Stecke, England, is a tyrosine kinase inhibitor and can effectively inhibit the activities of human epidermal growth factor receptor-1 (ErbB1) and human epidermal growth factor receptor-2 (ErbB2) tyrosine kinase. In 3 months 2007, lapatinib monohydrate, developed by Kurarin Shick corporation, was approved by the U.S. FDA for formal entry into clinical use for the treatment of advanced and metastatic breast cancer that is over-expressed by HER2 and is treated with anthracyclines, taxanes, trastuzumab, and the like at a precancerous stage.
The structural formula of lapatinib is as follows:
the inventor of the application combines virus RNA level analysis, titer determination and MTT determination cell viability detection methods to perform anti-enterovirus activity research experiments on lapatinib small molecular compounds, and data analysis in the embodiment adopts Graphpad software to perform statistical analysis, so that lapatinib is found to have a strong inhibition effect on enteroviruses. The enterovirus includes at least one of enterovirus 71, coxsackievirus B3 and coxsackievirus B4.
Lapatinib was evaluated for its inhibitory activity against EV71 virus and tested for activity by standard antiviral activity test methods. Through a large number of biological experiments, lapatinib is found to have good activity of inhibiting EV71 replication, and specifically shows that the lapatinib can inhibit intracellular nucleic acid replication and viral protein expression of EV71 virus, so that the virus proliferation is inhibited.
The experimental result shows that lapatinib has strong antiviral activity on EV71, can remarkably inhibit cytopathic effect (CPE) of 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, lapatinib has a significant inhibition effect on replication of coxsackievirus B3 type (CVB3) and coxsackievirus B4 type (CVB4) under different concentration conditions.
In conclusion, the results of the invention show that the compound lapatinib has potential to prepare specific treatment medicines for resisting intestinal infection, and has good clinical application prospect.
The invention provides an application of lapatinib in preparation of an anti-EV 71 virus drug, wherein the application refers to that lapatinib is added with pharmaceutically acceptable auxiliary materials and carriers and is used for preparing 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 drug dosage forms. The preparation is granule, tablet, pill, capsule, injection or dispersant.
It can be understood that the application of lapatinib as a lead compound for further structural optimization in preparing a medicament for treating enterovirus infectious diseases also belongs to the protection scope of the invention. Wherein the pharmaceutically acceptable derivative of lapatinib comprises: lapatinib ditosylate, lapatinib tosylate, a pharmaceutically acceptable salt of lapatinib, a pharmaceutically acceptable acid addition salt of lapatinib.
The application of lapatinib in the present application for preparing anti-enterovirus drugs will be described in detail below with reference to examples and experimental data.
Example 1 cytotoxicity assay for lapatinib
In RD cells, lapatinib cytotoxicity 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 lapatinib to be tested with different concentrations respectively to continue culturing, repeating 3 wells in each group, and adding PBS with the same amount in 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, the Prism7 software calculates the half-toxic concentration (CC) of the drug to the cell 50 ) CC of lapatinib 50 41368 nM. In the subsequent examples, lapatinib was used at a maximum concentration of 20000nM, within a safe and non-toxic range.
Example 2 inhibition of cytopathic effects of EV71 Virus replication by Lapatinib
RD cells were plated in 96-well plates at 37 ℃ with 5% CO 2 After 12-16h of culture in an incubator, 100TCID 50 The EV71 virus liquid infects cells for 2h, cell maintenance liquid containing test lapatinib with different concentrations is added respectively to continue culturing for about 48h, and PBS with the same volume is added as a negative control. When the virus control wells showed CPE lesions in about 90%, cytopathic effect (CPE) was observed under a microscope.
And (4) analyzing results: the detection result is shown in fig. 2, the lapatinib concentration-dependent mode inhibits RD cell CPE effect caused by EV71, RD cells infected by EV71 become round and are separated from cell plate walls, and experimental compound treatment at different concentrations has a remarkable inhibition effect on the pathological effect of RD cells, so that apoptosis generated by EV71 infection on RD cells is effectively protected.
Example 3 detection of EV71 antiviral Activity inhibited by Lapatinib
RD cells were seeded in 24-well plates at 37 ℃ with 5% CO 2 Culturing in incubator for 12-16h, using 100TCID 50 2h after infection with EV71 virus, cell maintenance solutions containing different concentrations of experimental lapatinib were used for treatment, and the same volume of PBS was added as the negative control. After 24h of treatment, the effect of inhibiting virus proliferation was detected by real-time fluorescent quantitative PCR.
And (4) analyzing results: the detection result is shown in fig. 3, and the compound lapatinib has a significant inhibition effect on the replication of EV71 under different concentration conditions. The lapatinib is used as an anti-EV 71 virus drug, and the inhibition rate of the lapatinib on EV71 virus is 93.9% when the concentration of the lapatinib is 20 mu M.
Example 4 detection of inhibition of EV71 proliferation Activity by Lapatinib
RD cells were seeded in 24-well plates at 37 ℃ with 5% CO 2 Culturing in incubator for 12-16h, and culturing with 100TCID 50 2h after infection with EV71 virus, cell maintenance solutions containing different concentrations of experimental lapatinib were used for treatment, and the same volume of PBS was added as the negative control. After 24h of treatment, the effect of inhibiting virus proliferation was examined by titer.
And (4) analyzing results: as shown in fig. 4, under different concentration conditions, the compound lapatinib treated EV 71-infected RD cells showed a significant reduction of viral particles in the culture supernatant compared to the treated cell group.
Example 5 Effect of lapatinib on EV71 replication
The experiment detects that lapatinib has good inhibitory activity on EV 71:
RD cells were seeded in 24-well plate cell culture plates at 37 ℃ with 5% CO 2 Culturing in incubator for 12-16h, and culturing with 100TCID 50 2h after infection with EV71 virus, treatment was performed with test compound (lapatinib) containing different concentrations, and the negative control was added to the same volume of PBS. After 24h of treatment, the effect of lapatinib in 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. 5, the influence of lapatinib on EV71 replication is shown, and lapatinib has a remarkable inhibition effect on EV71 replication under different concentration conditions.
Example 6 Effect of lapatinib 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 with 100TCID 50 After 2h infection with CVB3 and CVB4 virus solutions, respectively, treatment was performed with test compounds (lapatinib) containing different concentrations, and the negative control was added to the same volume of cell maintenance solution without lapatinib. After 17h of treatment, the effect of lapatinib on inhibiting virus replication is detected by a real-time fluorescent quantitative PCR (qPCR) method.
And (4) analyzing results: the detection results are shown in fig. 6, fig. 6A shows the influence of lapatinib on CVB3 replication, fig. 6B shows the influence of lapatinib on CVB4 replication, and lapatinib has significant inhibition effect on CVB3 and CVB4 replication under different concentration conditions.
In conclusion, lapatinib has remarkable activity of inhibiting EV71 and CVB4 replication, wherein lapatinib has the best inhibition effect, can strongly inhibit RD cytopathic effect caused by EV71 viruses, and enhances cell survival rate; inhibiting the replication of the viral RNA level and having the potential to further develop and prepare a medicament which is clinically effective for resisting the enterovirus infection.
Finally, it should also be 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 preferred embodiments and all such alterations and modifications as 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. The application of lapatinib in preparing anti-enterovirus medicines is characterized in that the enterovirus is at least one selected from enterovirus 71, coxsackievirus B3 and coxsackievirus B4.
2. The use of claim 1, wherein the anti-enterovirus medicament further comprises pharmaceutically acceptable excipients and carriers.
3. Use according to claim 2, wherein the excipient is selected from at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener or a colorant.
4. The use according to claim 1, wherein the anti-enterovirus drug is in a dosage form selected from at least one of granules, tablets, pills, capsules, injections or dispersions.
5. The use according to claim 4, 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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