CN105726525A - Application of compound containing Merochlorin A structure in preparation of medicines of resisting ebola virus infection - Google Patents
Application of compound containing Merochlorin A structure in preparation of medicines of resisting ebola virus infection Download PDFInfo
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- CN105726525A CN105726525A CN201610172559.1A CN201610172559A CN105726525A CN 105726525 A CN105726525 A CN 105726525A CN 201610172559 A CN201610172559 A CN 201610172559A CN 105726525 A CN105726525 A CN 105726525A
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Abstract
The invention discloses an application of a compound containing a Merochlorin A structure in preparation of medicines of resisting ebola virus infection. The compound containing the Merochlorin A structure is the compound shown in the formula (I). An experiment proves that the compound containing the Merochlorin A structure is capable of suppressing the infection effect of an ebola pseudovirus on an HUH7 cell before and after ebola pseudovirus infection, so that the compound containing the Merochlorin A structure is capable of preventing an ebola virus from infecting a target cell, and has important application value in preparation of the medicines of resisting ebola virus infection.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to a kind of new application of compound containing MerochlorinA structure, be more particularly to the application in preparing anti-Ebola virus infection medicine of the compound containing MerochlorinA structure.
Background technology
Ebola virus (EbolaVirus, EBOV) it is the pathogen of infectious disease ebola hemorrhagic fever, this hemorrhagic fever found in Zaire first in 1976, and the eruption and prevalence of its highly infective and high lethal quickly cause the attention of countries in the world research worker.Ebola virus has extremely strong infectivity, can cause the hemorrhagic fever syndrome of the mankind and other primate high lethal.Research shows, advancing of disease is had certain facilitation by all components of Ebola virus, especially membrane glycoprotein (the Glycoprotein of Ebola virus, GP) can adsorb with target cell, and then enter target cell, enter in target cell process at mediate retroviral and play a significant role.The membrane glycoprotein of Ebola virus is considered as determine the pathogenic key factor of Ebola virus; external by transfecting the plasmid encoding envelope glycoprotein gene or adenovirus entrance target cell; can result in coming off of target cell; show that the membrane glycoprotein of Ebola virus has cytotoxicity, but its mechanism is not quite clear.Visible, it is suppressed that the membrane glycoprotein activity of Ebola virus is to suppress the important channel of Ebola virus target cell infection.
Summary of the invention
How the technical problem to be solved prepares anti-Ebola virus infection medicine.
For solving the problems referred to above, present invention firstly provides the application in preparing anti-Ebola virus infection medicine of the compound containing MerochlorinA structure.
Described anti-Ebola virus infection medicine can be therapeutic type anti-Ebola virus infection medicine and/or the anti-Ebola virus infection medicine of prevention type.
Compound containing MerochlorinA structure suppresses the application that Ebola virus is infected in the product of mammalian cell to fall within protection scope of the present invention in preparation.
Described mammalian cell concretely people's cell.Described mammalian cell concretely mammalian hepatoma cells.Described mammalian cell concretely human liver cancer cell.Described human liver cancer cell concretely HUH7 cell.
Compound containing MerochlorinA structure suppresses the application in the product of the activity of the membrane glycoprotein of Ebola virus to fall within protection scope of the present invention in preparation.
In above-mentioned application, the membrane glycoprotein of described Ebola virus can be a1) or a2):
A1) aminoacid sequence is the protein shown in sequence 2；
A2) by a1) shown in the protein relevant to the membrane glycoprotein function of Ebola virus that obtains through the replacement of one or several amino acid residue and/or disappearance and/or interpolation of protein.
In any of the above-described described application, the described compound containing MerochlorinA structure can for compound shown in formula I；
For solving the problems referred to above, present invention also offers a kind of product.
Product provided by the present invention, its active component is the compound containing MerochlorinA structure；Described product can be following b1) or b2) or b3):
B1) anti-Ebola virus infection medicine；
B2) Ebola virus is suppressed to infect the product of mammalian cell；
B3) product of the activity of the membrane glycoprotein of Ebola virus is suppressed.
In the said goods, described anti-Ebola virus infection medicine can be therapeutic type anti-Ebola virus infection medicine and/or the anti-Ebola virus infection medicine of prevention type.
In the said goods, described mammalian cell concretely people's cell.In the said goods, described mammalian cell concretely mammalian hepatoma cells.In the said goods, described mammalian cell concretely human liver cancer cell.Described human liver cancer cell concretely HUH7 cell.
In the said goods, the membrane glycoprotein of described Ebola virus can be a1) or a2):
A1) aminoacid sequence is the protein shown in sequence 2；
A2) by a1) shown in the protein relevant to the membrane glycoprotein function of Ebola virus that obtains through the replacement of one or several amino acid residue and/or disappearance and/or interpolation of protein.
In any of the above-described described product, the described compound containing MerochlorinA structure can for compound shown in formula I；
Any of the above-described described Ebola virus can be Zaire's hypotype, is specially H.sapienswt/GIN/2014/Gueckedou-C07.
Due to highly pathogenic and infectiousness, heretofore described Ebola virus can use Ebola's pseudovirus to replace, and the preparation method of described Ebola's pseudovirus can be as follows:
1, to plasmid pcDNATMInserting nucleotide sequence between the recognition sequence of restricted enzyme BamHI and XhoI of 4/HisMax is the double chain DNA molecule shown in sequence 1 in sequence table, obtains recombiant plasmid pcDNA4-EBOV-GP.
2, by recombiant plasmid pcDNA4-EBOV-GP and pNL4.3-Luc-R-E-vector plasmid cotransfection HEK293T cell, it is placed in 37 DEG C, 5%CO2Incubator hatches 6h, rinses 2 times with PBS, is subsequently adding DMEM culture medium, is placed in 37 DEG C, 5%CO2Incubator continues to hatch 48h, collects cell conditioned medium.
3, taking the cell conditioned medium that step 2 is collected, 3000rpm is centrifuged 10min, collects supernatant and with 0.22 μm of filtering with microporous membrane, collects the liquid after filtering.
4, take step 3 filter after liquid, 30000rpm be centrifuged 2.5h, it is thus achieved that precipitation with 1mLDMEM culture medium dissolving, obtain the virus liquid of described Ebola's pseudovirus.
In sequence table, the membrane glycoprotein of the Ebola virus shown in sequence 2 is the membrane glycoprotein of the H.sapienswt/GIN/2014/Gueckedou-C07 of Zaire's hypotype of Ebola virus.Therefore, containing the compound of MerochlorinA structure, there is suppression and there is the ability of the pseudovirus of the membrane glycoprotein of the Ebola virus shown in sequence 2 in sequence table, it should also there is the ability of the Ebola virus suppressing Zaire's hypotype.The Ebola virus of Zaire's hypotype concretely H.sapienswt/GIN/2014/Gueckedou-C07.
It is demonstrated experimentally that the infection of Ebola's pseudovirus is respectively provided with inhibitory action before Ebola's pseudovirus infects or after infection by the compound containing MerochlorinA structure provided by the invention.Therefore, the compound containing MerochlorinA structure provided by the invention can suppress Ebola virus target cell infection, has important using value in preparing anti-Ebola virus infection medicine.
Accompanying drawing explanation
Fig. 1 gives the inhibitory action that Ebola's pseudovirus is infected HUH7 cell by compounds I before Ebola's pseudovirus infects.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention being further described in detail, the embodiment provided is only for illustrating the present invention, rather than in order to limit the scope of the present invention.
Experimental technique in following embodiment, if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, all commercially obtain.
HUH7 cell (human liver cancer cell), purchased from Japan's cell bank (JapaneseCollectionofResearchBioresources, JCRB), is numbered JCRB0403.Hyclone is SeraPro Products.DMEM culture medium is Gibco Products.Dimethyl sulfoxide is Amresco Products.LuciferaseCellCultureLysis5 × Reagent is Promega Products, and article No. is E1531.HEK293T cell is China General Microbiological preservation administrative center's (being called for short CGMCC) product, and catalog number is 8.00020.Plasmid pcDNATM4/HisMax is Lifetechnologies Products, and article No. is V86420.PBS is BioTopped Products, and article No. is top0027.LuciferaseAssaySystem10-Pack is Promega Products, and article No. is E1501.
The preparation method of ZMapp2G4 monoclonal antibody is with reference to such as Publication about Document: QXiangguo, WGary, etal.ReversionofadvancedEbolavirusdiseaseinnonhumanprima teswithZMapp.Nature.2014,514 (10): 47-61.
Purchased from BioVector China plasmid vector strain cell gene preservation center-NTCC country Type Tissue Collection, (network address is pNL4.3-Luc-R-E-vector plasmidhttp://www.biovector.net/), article No. is 3767994.
Embodiment 1, Ebola's pseudovirus diluent preparation method
Due to the highly pathogenic of Ebola virus and infectiousness, Ebola's pseudovirus can replace the part research of live virus.The preparation method of the Ebola's pseudovirus used in the present invention is as follows:
1, to plasmid pcDNATMInserting nucleotide sequence between the recognition sequence of restricted enzyme BamHI and XhoI of 4/HisMax is the double chain DNA molecule shown in sequence 1 in sequence table, obtains recombiant plasmid pcDNA4-EBOV-GP.The membrane glycoprotein (Glycoprotein, GP) of the Ebola virus shown in sequence 2 in recombiant plasmid pcDNA4-EBOV-GP expressed sequence table, hereinafter referred to as GP albumen.
2, recombiant plasmid pcDNA4-EBOV-GP step 1 built and pNL4.3-Luc-R-E-vector plasmid cotransfection HEK293T cell (every 1 × 106Individual HEK293T cell about transfects 10 μ g recombiant plasmid pcDNA4-EBOV-GP and 10 μ gpNL4.3-Luc-R-E-vector plasmids), it is placed in 37 DEG C, 5%CO2Incubator hatches 6h, rinses 2 times with PBS, is subsequently adding DMEM culture medium, is placed in 37 DEG C, 5%CO2Incubator continues to hatch 48h, collects cell conditioned medium.
3, taking the cell conditioned medium that step 2 is collected, 3000rpm is centrifuged 10min, collects supernatant and with 0.22 μm of filtering with microporous membrane, collects the liquid after filtering.
4, take step 3 filter after liquid, 30000rpm be centrifuged 2.5h, it is thus achieved that precipitation with 1mLDMEM culture medium dissolving, obtain the virus liquid of Ebola's pseudovirus.The virus liquid of this Ebola's pseudovirus can express GP albumen.
Take the virus liquid of Ebola's pseudovirus, be diluted to 35 times of volumes by DMEM culture medium, obtain Ebola's pseudovirus diluent.
Embodiment 2, prepare compounds I
According to document (PepperHP, GeorgeJH.Biomimetictotalsynthesisof (±)-merochlorinA.AngewChemIntEdEng.2013；52 (46): 12170-3.) method recorded in prepares compounds I.The structural formula of compounds I is such as shown in formula I, and its name in the literature is called MerochlorinA.
Embodiment 3, compounds I suppress Ebola's pseudovirus to infect HUH7 cell
Adopt compounds I as reagent, carrying out experiment as follows:
One, Ebola's pseudovirus is administered the depression effect to Ebola's pseudovirus before infecting
Arranging test group, carry out three repeated trials, the step of each repeated trials is all as follows:
1, with trypsinization HUH7 cell, then resuspended by the DMEM culture medium containing 10% (volume ratio) hyclone and dilute, it is thus achieved that cell density is 1 × 105The cell suspending liquid of individual/mL.
2, dissolve for reagent with dimethyl sulfoxide (DMSO), it is thus achieved that for reagent solution.
3, taking 96 orifice plates, the cell suspending liquid that 100 μ L steps 1 obtain is inoculated in every hole, is subsequently placed in 37 DEG C, 5%CO2Incubator in cultivate 12h.
4, after completing step 3, take described 96 orifice plates, abandon supernatant, every hole adds DMEM culture medium 100 μ L, what add step 2 preparation supplies reagent solution, and (concentration for reagent in system for handling is 23.312 μMs, 5.828 μMs, 1.458 μMs, 0.364 μM or 0.09 μM to obtain system for handling；Each concentration arranges 4 multiple holes), it is subsequently placed in 37 DEG C, 5%CO2Incubator in cultivate 30min.
5, after completing step 4, taking described 96 orifice plates, every hole adds Ebola's pseudovirus diluent of 100 μ L embodiment 1 preparations, is placed in 37 DEG C, 5%CO2Incubator in hatch 6h.
6, taking described 96 orifice plates, inhale the liquid abandoning in hole, every hole adds 100 μ LPBS buffer solution once；Then every hole adds the 100 μ L DMEM culture medium containing 5% (volume ratio) hyclone, cultivates 48h for 37 DEG C.
7, taking described 96 orifice plates, inhale the liquid abandoning in hole, every hole adds 100 μ LPBS buffer solution once.
8, after completing step 7, taking described 96 orifice plates, every hole adds 30 μ LLuciferaseCellCultureLysis5 × Reagent, cracks 30min.
9, after completing step 8, take described 96 orifice plates, add LuciferaseAssaySystem10-Pack, adopt fluorescence microplate reader detection fluorescent value.
Negative control group is set: replacing for reagent solution with equal-volume dimethyl sulfoxide, other operates same test group.4 multiple holes are set.
Positive controls is set: replacing for reagent solution by equal-volume ZMapp2G4 monoclonal antibody, other operates same test group.In positive controls, the concentration of ZMapp2G4 monoclonal antibody is 66.667 μMs.4 multiple holes are set.
The suppression ratio of HUH7 cell after confession reagent process according to following formula calculating variable concentrations:
Detection fluorescent value × 100% of suppression ratio=(the detection fluorescent value of the detection fluorescent value-test group of negative control group)/negative control group.
The experimental result of the suppression ratio of Ebola's pseudovirus host cells infected is shown in Fig. 1 (being abscissa for reagent concentration denary logarithm value in system for handling, it is suppressed that rate is vertical coordinate) by compounds I.It is shown that along with the increase of compounds I concentration in system for handling, it is suppressed that rate also increases.Visible, Ebola's pseudovirus gives compounds I before infecting can suppress the dissemination to HUH7 cell of Ebola's pseudovirus.
Two, Ebola's pseudovirus is administered the depression effect to Ebola's pseudovirus after infecting
Arranging test group, carry out three repeated trials, the step of each repeated trials is all as follows:
1, with trypsinization HUH7 cell, then resuspended by the DMEM culture medium containing 10% (volume ratio) hyclone and dilute, it is thus achieved that cell density is 1 × 105Individual/cm2Cell suspending liquid.
2, taking 96 orifice plates, the cell suspending liquid that 100 μ L steps 1 obtain is inoculated in every hole, is subsequently placed in 37 DEG C, 5%CO2Incubator in cultivate 12h.
3, dissolve for reagent with dimethyl sulfoxide (DMSO), it is thus achieved that for reagent solution.
4, one 96 orifice plates are separately taken, every hole adds Ebola's pseudovirus diluent of 100 μ L steps one preparations and the confession reagent solution of step 3 preparation, and (concentration for reagent in system for handling is 11.656 μMs, 0.729 μM, 0.182 μM or 0.045 μM to obtain system for handling；Each concentration arranges 4 multiple holes), it is subsequently placed in 37 DEG C, 5%CO2Incubator in cultivate 30min, obtain mixed liquor.
5, taking into 96 orifice plates after step 2, inhale the liquid abandoning in hole, every hole adds 100 μ LPBS buffer solution once；Then every hole adds the mixed liquor of 100 μ L step 4 preparations, is placed in 37 DEG C, 5%CO2Incubator in cultivate 6h.
6, after completing step 5, taking described 96 orifice plates, inhale the liquid abandoning in hole, every hole adds 100 μ LPBS buffer solution once, and then every hole adds the 100 μ L DMEM culture medium containing 5% (volume ratio) hyclone, cultivates 48h for 37 DEG C.
7, after completing step 6, taking described 96 orifice plates, every hole adds 30 μ LLuciferaseCellCultureLysis5 × Reagent, cracks 30min.
8, after completing step 7, take described 96 orifice plates, add LuciferaseAssaySystem10-Pack, adopt fluorescence microplate reader detection fluorescent value.
Negative control group is set: replacing for reagent solution with equal-volume dimethyl sulfoxide, other operates same test group.4 multiple holes are set.
Positive controls is set: replacing for reagent solution by equal-volume ZMapp2G4 monoclonal antibody, other operates same test group.In positive controls, the concentration of ZMapp2G4 monoclonal antibody is 66.667 μMs.4 multiple holes are set.
The suppression ratio of HUH7 cell after confession reagent process according to following formula calculating variable concentrations:
Detection fluorescent value × 100% of suppression ratio=(the detection fluorescent value of the detection fluorescent value-test group of negative control group)/negative control group.
For reagent to the experimental result of the suppression ratio of Ebola's pseudovirus in Table 1.It is shown that along with the increase for reagent concentration in system for handling, it is suppressed that rate also increases.Visible, the dissemination to HUH7 cell of Ebola's pseudovirus can be suppressed for reagent.
Table 1. is for the reagent inhibitory action to Ebola's pseudovirus host cells infected
Claims (10)
1. containing the application in preparing anti-Ebola virus infection medicine of the compound of MerochlorinA structure.
2. suppress Ebola virus to infect the application in the product of mammalian cell containing the compound of MerochlorinA structure in preparation.
3. apply as claimed in claim 2, it is characterised in that: described mammalian cell is human liver cancer cell.
4. containing the compound of MerochlorinA structure preparation suppress Ebola virus membrane glycoprotein activity product in application.
5. apply as claimed in claim 4, it is characterised in that: the membrane glycoprotein of described Ebola virus is a1) or a2):
A1) aminoacid sequence is the protein shown in sequence 2；
A2) by a1) shown in the protein relevant to the membrane glycoprotein function of Ebola virus that obtains through the replacement of one or several amino acid residue and/or disappearance and/or interpolation of protein.
6. the application as described in as arbitrary in claim 1 to 5, it is characterised in that: the described compound containing MerochlorinA structure is compound shown in formula I；
7. a product, its active component is the compound containing MerochlorinA structure；Described product is following b1) or b2) or b3):
B1) anti-Ebola virus infection medicine；
B2) Ebola virus is suppressed to infect the product of mammalian cell；
B3) product of the activity of the membrane glycoprotein of Ebola virus is suppressed.
8. product as claimed in claim 7, it is characterised in that: in described b2), described mammalian cell is human liver cancer cell.
9. product as claimed in claim 7, it is characterised in that: in described b3), the membrane glycoprotein of described Ebola virus is a1) or a2):
A1) aminoacid sequence is the protein shown in sequence 2；
A2) by a1) shown in the protein relevant to the membrane glycoprotein function of Ebola virus that obtains through the replacement of one or several amino acid residue and/or disappearance and/or interpolation of protein.
10. the product as described in as arbitrary in claim 7 to 9, it is characterised in that:
The described compound containing MerochlorinA structure is compound shown in formula I；
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| CN201610172559.1A CN105726525B (en) | 2016-03-24 | 2016-03-24 | Application of the compound of the structures of A containing Merochlorin in preparing anti-Ebola virus infection medicine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999284A (en) * | 2018-01-25 | 2022-02-01 | 中国医学科学院医药生物技术研究所 | Cyclic polypeptide for resisting Ebola virus or medicinal salt thereof |
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2016
- 2016-03-24 CN CN201610172559.1A patent/CN105726525B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| G SAKOULAS等: "Novel Bacterial Metabolite Merochlorin A Demonstrates in vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus", 《PLOS ONE》 * |
| 曹瑞源等: "抗埃博拉病毒小分子抑制剂的研究进展", 《国际药学研究杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999284A (en) * | 2018-01-25 | 2022-02-01 | 中国医学科学院医药生物技术研究所 | Cyclic polypeptide for resisting Ebola virus or medicinal salt thereof |
| CN113999284B (en) * | 2018-01-25 | 2024-05-17 | 中国医学科学院医药生物技术研究所 | Cyclic polypeptides or pharmaceutically acceptable salts thereof for use against ebola virus |
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| CN105726525B (en) | 2018-09-25 |
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