CN113332286A - Application of Onalesipb compound in preparation of anti-EV 71 virus medicine - Google Patents
Application of Onalesipb compound in preparation of anti-EV 71 virus medicine Download PDFInfo
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- CN113332286A CN113332286A CN202110509408.1A CN202110509408A CN113332286A CN 113332286 A CN113332286 A CN 113332286A CN 202110509408 A CN202110509408 A CN 202110509408A CN 113332286 A CN113332286 A CN 113332286A
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- 239000003814 drug Substances 0.000 title claims abstract description 24
- 241000700605 Viruses Species 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 241001529459 Enterovirus A71 Species 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 14
- -1 Onalespib compound Chemical class 0.000 claims abstract description 4
- 229950000307 onalespib Drugs 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000002270 dispersing agent Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
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- 239000003826 tablet Substances 0.000 claims description 3
- IFRGXKKQHBVPCQ-UHFFFAOYSA-N onalespib Chemical class C1=C(O)C(C(C)C)=CC(C(=O)N2CC3=CC(CN4CCN(C)CC4)=CC=C3C2)=C1O IFRGXKKQHBVPCQ-UHFFFAOYSA-N 0.000 claims 2
- 230000000120 cytopathologic effect Effects 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000004083 survival effect Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 21
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000020061 Hand, Foot and Mouth Disease Diseases 0.000 description 3
- 208000025713 Hand-foot-and-mouth disease Diseases 0.000 description 3
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- 231100000135 cytotoxicity Toxicity 0.000 description 3
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- 239000002356 single layer Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
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- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
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- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 206010027201 Meningitis aseptic Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
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- 230000005923 long-lasting effect Effects 0.000 description 1
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- 210000000064 prostate epithelial cell Anatomy 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 241000701161 unidentified adenovirus Species 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention discloses an application of a Onalespib compound in preparing an anti-EV 71 virus medicament. Through AT13387 anti-EV 71 activity research experiments, the compound AT13387 inhibits cytopathic effect (CPE) generated by EV71 on a host cell RD, enhances cell survival rate, reduces yield of progeny virus, and can be applied to preparation of anti-EV 71 virus medicines.
Description
Technical Field
The invention belongs to the technical field of antiviral drugs, and particularly relates to an application of a Onalesib compound in preparation of an anti-EV 71 virus drug.
Background
Enterovirus type 71 (EV71), a member of the Enterovirus genus (Enterovirus) of the Picornaviridae family (Picornaviridae), is one of the most prominent pathogens causing hand-foot-and-mouth disease in infants and young children, sometimes with severe central nervous system complications including aseptic meningitis, encephalitis, polio-like paralysis, neurological heart-lung failure, etc., and even death. The government of China has listed the hand-foot-and-mouth disease as a class C infectious disease in 2008 and brings into management, and a series of relevant laws and regulations are formulated to strictly control the epidemic spread of the hand-foot-and-mouth disease. There is currently no specific drug for the treatment of diseases infected by EV71, and related vaccines are marketed in 2015, and their preventive effects are yet to be further investigated. Therefore, the development of specific and effective anti-EV 71 medicaments is imperative.
Onalesib (AT13387) is a potent, selective inhibitor of Hsp90, IC in A375 cells50Is 18nM and has long-lasting antitumor activity. AT13387 inhibited various kinases including CDK 1, CDK2, CDK4, FGFR3, etc., but AT13387 concentrations below 30 μ M had no significant inhibitory effect on the experimental kinases. AT13387 is effective in inhibiting proliferation and survival of a variety of tumor cell lines, such as MES-SA cell lines. AT13387 acts on 30 tumor cell lines to effectively inhibit cell proliferation, GI50Values were 13-260 nM. AT13387 inhibits proliferation of the non-tumorigenic prostate epithelial cell line PNT2, GI50The value was 480 nM. However, the use of AT13387 for antiviral therapy has been rarely reported.
Disclosure of Invention
Aiming AT the defects of the prior art, the invention aims to evaluate the inhibitory activity of AT13387 on EV71 virus, and aims to provide the application of Onalespib compound in preparing anti-EV 71 virus medicines, namely AT13387 is used as an anti-EV 71 virus screening compound.
In order to achieve the purpose, the invention provides an application of Onalesib compound in preparing anti-EV 71 virus medicines, which is characterized in that: the Onalesib compound (AT13387) (C) having anti-EV 71 activity24H31N3O3) The chemical structural formula is as follows:
preferably, the Onalespib compound inhibits EV71 at 6.25. mu.M by 65%.
Furthermore, the medicine is prepared into a preparation for resisting EV71 virus by adding pharmaceutically acceptable auxiliary materials and carriers into the Onalesib compound.
Further, the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
The invention has the following advantages and beneficial effects:
the object of the invention is achieved in that AT13387 is tested for its activity by standard viral activity test methods. According to the invention, through a large number of biological experiments, AT13387 has activity against EV71 virus. The recombinant adenovirus can inhibit cytopathic effect caused by EV71 virus, enhance the survival rate of infected cells, inhibit the replication and proliferation of EV71 virus in cells, and reduce the yield of progeny virus. Therefore, the compound has potential to prepare specific therapeutic drugs for resisting EV71 infection and has a great clinical application prospect.
Drawings
FIG. 1 is a graph of the effect of AT13387 on RD cell viability with EV71 action.
FIG. 2 shows the inhibitory effect of AT13387 on RD cell CPE caused by EV 71.
FIG. 3 shows the inhibitory effect of AT13387 on the yield of EV71 progeny virus.
FIG. 4 shows the chemical formula of AT 13387.
Detailed Description
AT13387 used in the present invention was obtained from reagent company. The invention relates to application of AT13387 in preparation of an anti-EV 71 virus medicament, which is to add pharmaceutically acceptable auxiliary materials and carriers to AT13387 for preparing an anti-EV 71 virus preparation. The preparation is granule, tablet, pill, capsule, injection or dispersant.
AT13387 of the present invention has the following chemical structure:
the application of the AT13387 disclosed by the invention as the anti-EV 71 virus shows that the AT13387 has obvious effect on resisting the EV71 virus. Therefore, the compound has potential to prepare specific therapeutic drugs for resisting EV71 infection and has a great clinical application prospect.
Example 1
The invention carries out anti-EV 71 activity research experiments on the compounds, and the experimental conditions are as follows: hereinafter, materials and operation methods used in the present invention are well known in the art, if not specifically described.
1. The test contents are as follows:
analysis of compound anti-EV 71 activity: the invention combines the cytopathic effect analysis and the MTT determination cell survival rate detection method to evaluate the activity of AT13387 against EV 71.
2. The test method comprises the following steps:
2.1.1 toxicity of Compounds on host RD cells
RD cells were plated in 96-well plates at 37 ℃ with 5% CO2After the culture box is cultured to grow a monolayer, cell culture solution is discarded, cell maintenance solutions containing test compounds with different concentrations are respectively added for continuous culture, the cytotoxicity is visually observed and respectively recorded by a microscope after 48 hours, and the cell survival rate is measured by an MTT method. The SPSS 11.5 software calculates the Median cytotoxic concentration of the drug for the cells (CC 50). Cell survival rate ═ (mean OD of drug groups)492Value/cell control mean OD492Value) × 100%.
2.1.2 inhibitory Activity of Compounds on EV71
RD cells were plated in 96-well plates at 37 ℃ with 5% CO2After the incubator is used for culturing full monolayer, the culture solution is discarded, cells are infected by EV71 virus solution of 100TCID50 for 1.5h, and test compounds (ribavirin serving as a positive control drug) with different concentrations are added for cell incubation. After the culture is continued for about 48 hours, the cytopathic effect (CPE) is observed under a microscope when about 90% of CPE lesions appear in the virus control wells. Observation and recording method of CPE: no cytopathic effect is recorded as-below 25% cytopathic effect, 25% -50% cytopathic effect is recorded as +++, 50% -75% cytopathic effect is recorded as +++, and more than 75% cytopathic effect is recorded as ++++.
After CPE is observed, the method utilizesThe MTT method measures the inhibition rate of EV71 by the drug. The method comprises the following specific steps: MTT 50. mu.L (5 mg. multidot.mL) was added to each well-1) After incubation for 3-4h, the supernatant was removed and an equal volume of DMSO was added to dissolve the pellet. The absorbance (OD) at 492nm was read with a microplate reader492Value). The inhibition rate of the drug on EV71 was calculated using the following formula. The half effective Concentration of the drug (Concentration for 50% of maximum effect, EC50) was calculated using SPSS 11.5 software.
2.1.3 Therapeutic Index (TI) of drug
TI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
3. Results of the experiment
TABLE 1 AT13387 cytotoxicity and anti-EV 71 Activity
The results of the compound cytotoxicity and anti-EV 71 activity tests are shown in table 1. The effect of concentration-dependent compounds on RD cell viability with EV71 action is shown in figure 1. The maximum inhibition rate of AT13387 AT 6.25. mu.M was found to be about 65%.
Example 2
The invention carries out the intensive research on the anti-EV 71 activity of AT13387, and carries out the test of the inhibitory effect of the compound on the yield of EV71 progeny virus, wherein the test conditions are as follows:
1. content of the experiment
Compounds were tested for inhibition of EV71 progeny virus production following EV71 infection of RD cells.
2. Test method
RD cells in logarithmic growth phase are plated on 24-well plates and 100TCID after full monolayer growth50EV71 infected cells were incubated at 37 ℃ for 1.5h, virus fluid was removed, washed three times with PBS, and cell maintenance fluid containing 6.25. mu.M was added. After 48h, cells were harvested and platedClear culture medium, after three times of freeze thawing and lysis at-20 ℃ and 37 ℃, TCID50Methods EV71 virus titers were determined.
3. Test results
As shown in fig. 3, compound-treated RD cells all had a significant reduction in viral titer over the viral control, which was more than 4.9log reduction over the viral control.
In conclusion, AT13387 has strong EV71 inhibiting activity, can inhibit RD cytopathic effect caused by EV71 virus, and can be prepared into a medicament for clinically and effectively resisting EV71 infection.
Claims (4)
1. The application of the Onalesib compound in preparing the anti-EV 71 virus medicine is characterized in that: the Onalesib compound with the anti-EV 71 activity has the following chemical structural formula:
2. the use of Onalespib compounds according to claim 1 for the preparation of anti-EV 71 virus medicaments, characterized in that: the Onalesib compound inhibited EV71 at 6.25. mu.M by 65%.
3. Use of Onalespib compounds according to claim 1 or 2 for the preparation of a medicament against EV71 virus, characterized in that: the medicine is prepared by adding pharmaceutically acceptable auxiliary materials and carriers into the Onalesib compound to prepare a preparation for resisting EV71 virus.
4. The use of Onalespib compound of claim 3 in the preparation of a medicament against EV71 virus, wherein: the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110509408.1A CN113332286A (en) | 2021-05-11 | 2021-05-11 | Application of Onalesipb compound in preparation of anti-EV 71 virus medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110509408.1A CN113332286A (en) | 2021-05-11 | 2021-05-11 | Application of Onalesipb compound in preparation of anti-EV 71 virus medicine |
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| CN113332286A true CN113332286A (en) | 2021-09-03 |
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| CN202110509408.1A Pending CN113332286A (en) | 2021-05-11 | 2021-05-11 | Application of Onalesipb compound in preparation of anti-EV 71 virus medicine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114767683A (en) * | 2022-04-29 | 2022-07-22 | 暨南大学 | Application of Onalesipi b in preparation of medicine for preventing and/or treating adenovirus infection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668015A (en) * | 2016-12-21 | 2017-05-17 | 湖北工业大学 | Application of fatty-based ester compound WY124 in preparing anti-enterovirus drug |
-
2021
- 2021-05-11 CN CN202110509408.1A patent/CN113332286A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668015A (en) * | 2016-12-21 | 2017-05-17 | 湖北工业大学 | Application of fatty-based ester compound WY124 in preparing anti-enterovirus drug |
Non-Patent Citations (1)
| Title |
|---|
| 李妮: ""药物新适应症的开发——抗肠道病毒EV71 的功效评价及机理研究"" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114767683A (en) * | 2022-04-29 | 2022-07-22 | 暨南大学 | Application of Onalesipi b in preparation of medicine for preventing and/or treating adenovirus infection |
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