CN107929300A - Feldamycin is preparing relevant disease caused by treatment dengue virus infection and/or the application in the medicine of symptom - Google Patents
Feldamycin is preparing relevant disease caused by treatment dengue virus infection and/or the application in the medicine of symptom Download PDFInfo
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- CN107929300A CN107929300A CN201711009977.XA CN201711009977A CN107929300A CN 107929300 A CN107929300 A CN 107929300A CN 201711009977 A CN201711009977 A CN 201711009977A CN 107929300 A CN107929300 A CN 107929300A
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- LUOBEJSTJAVJPL-UHFFFAOYSA-N feldamycin Chemical compound C=1NC=NC=1CC(C(O)=O)NC(C)C(C(O)=O)NC(=O)C(NC)CC1=CNC=N1 LUOBEJSTJAVJPL-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 206010012310 Dengue fever Diseases 0.000 title claims abstract description 8
- 208000025729 dengue disease Diseases 0.000 title claims abstract description 8
- 201000010099 disease Diseases 0.000 title claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 7
- 238000011282 treatment Methods 0.000 title claims abstract description 7
- 208000024891 symptom Diseases 0.000 title claims abstract description 6
- 241000725619 Dengue virus Species 0.000 claims abstract description 16
- 101800000508 Non-structural protein 5 Proteins 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 5
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZVGNESXIJDCBKN-UUEYKCAUSA-N fidaxomicin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC\1=C/C=C/C[C@H](O)/C(C)=C/[C@@H]([C@H](/C(C)=C/C(/C)=C/C[C@H](OC/1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-UUEYKCAUSA-N 0.000 description 9
- 241000700605 Viruses Species 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- 229960000628 fidaxomicin Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- ZVGNESXIJDCBKN-WUIGKKEISA-N R-Tiacumicin B Natural products O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC1=CC=CC[C@H](O)C(C)=C[C@@H]([C@H](C(C)=CC(C)=CC[C@H](OC1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-WUIGKKEISA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 108700027092 dengue virus NS5 Proteins 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 208000037384 Clostridium Infections Diseases 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 206010054236 Clostridium difficile infection Diseases 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940004552 dificid Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses feldamycin to prepare relevant disease caused by treatment dengue virus infection and/or the application in the medicine of symptom, feldamycin is as the anti-C. difficile infection medicine used by clinical approval, it is safe, and feldamycin suppresses dengue virus activity height, there is stronger binding ability with dengue virus non-structural protein NS5, be expected to become new effective dengue virus infection medicine.
Description
Technical field
The invention belongs to field of medicaments, is being prepared more particularly, to feldamycin caused by treatment dengue virus infection
Application in relevant disease and/or the medicine of symptom.
Background technology
Feldamycin（Fidaxomicin）（Trade name Dificid, also known as difimicin, lipiarmycin,
Tiacumicin B, former name：PAR-101, OPT-80）It is a kind of RNase inhibitor of the DNA dependences of bacterium.By
Optimer companies, which develop, is used for initial treatment C. difficile infection（Clostridium difficile infection, CDI）
And prevention CDI recurrences, in January, 2011, food and drug administration（FDA）Pass through feldamycin to be used to treat children
The qualification application of CDI, in May, 2011, FDA have approved feldamycin and be used for CDI treatments of being grown up.
The structure of feldamycin is as follows：。
Dengue virus belongs to flaviviridae Flavivirus, is RNA positive strand viruses, by killing propagation, may occur in which systemic
Shock death can occur for the symptoms such as fever, eruption, arthritis, severe patient.
DENV-NS5 is a kind of RNA polymerase of RNA dependences, viral genome copy function is exercised, to virus replication
Play the role of it is most important, suppress this kind of enzymatic activity can reach kill dengue virus effect.
Currently for dengue virus, lack the clinical active drug ratified.
The content of the invention
It is an object of the invention to according to deficiency of the prior art, there is provided feldamycin is preparing suppression dengue virus
Application in medicine.
The present invention is achieved through the following technical solutions above-mentioned technical purpose：
The present invention provides feldamycin to prepare the application in suppressing dengue virus medicine.
Further, feldamycin is to prepare relevant disease and/or the medicine of symptom caused by treatment dengue virus infection
Application in thing.
Further, feldamycin is as dengue virus non-structural protein NS5（DENV-NS5）Inhibitor, plays and suppresses
The effect of dengue virus.
Further, RNase of the feldamycin as RNA dependences in DENV-NS5（DENV-NS5RdRp）Suppress
Agent.
The medicine further includes pharmaceutically acceptable salt or carrier.
Compared with prior art, the invention has the advantages that and beneficial effect：
The present invention provides feldamycin as the new opplication suppressed on dengue virus, feldamycin is as by clinic approval
The anti-C. difficile infection medicine used, it is safe, and feldamycin suppresses dengue virus activity height on a cellular level, with
DENV2-NS5 albumen has stronger binding ability, is expected to become new effective dengue virus infection medicine.
Brief description of the drawings
Fig. 1 is the expression that feldamycin suppresses DENV2 prM albumen in A549 cells.
Embodiment
Further illustrate the present invention below in conjunction with specific embodiments and the drawings, but embodiment the present invention is not done it is any
The restriction of form.Unless stated otherwise, the reagent of the invention used, method and apparatus is the art conventional reagent, methods
And equipment.
Unless stated otherwise, agents useful for same and material of the present invention are purchased in market.
Embodiment 1：The suppression dengue virus of feldamycin on a cellular level（DENV）Activity
Strain：Dengue virus DENV2（NGC）, cell line：A549
Detection method：
The antiviral median effective dose of feldamycin（50% Effective Concentration, EC50）：DMSO, 6,9,12,
18th, 24 μM of feldamycins shift to an earlier date 1h saturation cells, and after virus infects 2h, the virus-free culture medium for changing the medicine containing corresponding concentration maintains
48h；Cell conditioned medium is collected, feldamycin various dose group relative solvent group after virus infects is detected with plaque assay（DMSO）'s
Plaque test inhibiting rate.
Inhibiting rate（%） = （1- administration group virus plaques form number/solvent control group plaque test number）100%, use EXCEL
2013 Forcast formula calculate, when inhibiting rate is equal to 50%, the concentration of corresponding feldamycin, as EC50.Reality is repeated three times
Test and be averaged.
Feldamycin cell toxicant half cell active inhibitors amount（50% Cytotoxcitive Concentration,
CC50）：Mtt assay, feldamycin graded doses are added in A549 cell conditioned mediums, are added MTT incubation 4h after maintaining 48h, are suctioned out training
Base is supported, DMSO detections 490nm is added and goes out absorbance compared with DMSO solvent control groups, calculate inhibitor rate（%）=（1-
Administration group 490nm absorbances/solvent control group 490nm absorbances）100%, with the Forcast formula meters of EXCEL 2013
Calculate, when inhibiting rate is equal to 50%, the concentration of corresponding feldamycin, as CC50.Three repeated experiments are averaged.Obtain a result
Table 1：
Table 1：Feldamycin suppresses DENV EC in A549 cells50And CC50
| antiviral EC50（μM） | CC50（μM） | |
| DENV2（NGC） | A549 | |
| Fidaxomicin | 16.74±2.44 | 70.84±4.72 |
2 feldamycin of embodiment is in A549 cell lines to the inhibitory activity of DENV2-prM albumen
Strain：Dengue virus DENV2（NGC）
Cell line：A549
Detection method：
DMSO, 10,50,100 μM of feldamycins shift to an earlier date 1h saturation cells, after virus infects 2h, change the nothing of the medicine containing corresponding concentration
Virus culture base maintains 48h；Cell precipitation is collected, with intracellular DENV2 under protein immunoblotting electrophoresis detection different disposal
（NGC）The relative expression quantity of-prM albumen, internal reference albumen is used as using GAPDH.As shown in Figure 1, feldamycin is in 10 ~ 50 μM of concentration
Memebrane protein -- the DENV2-prM albumen of DENV can effectively be suppressed down, the important structural proteins DENV2- as composition virus
The expression of prM is suppressed, and illustrates that the breeding of DENV2 is suppressed.
3 surface plasma resonance of embodiment detects the affinity of feldamycin and DENV2-NS5 albumen
This method is tested using the Biacore T100 instruments and CM5 chips of GE companies, the DENV2 being first purified
（NGC）- NS5 histone aminos are coupled on CM5 chips, then flow through the feldamycin of various concentrations, instrument detection absorption is in core
The mass change of the material on piece surface, calculates the affine speed of compound（Ka）With dissociation rate（Kd）.Affinity=dissociation is put down
Weigh constant（KD）, which describes the bond strength between small molecule and protein molecular, and biological significance is, when small molecule and albumen
Matter 1：1 when combining, and allows the concentration of 50% small molecule saturation protein molecular, and the smaller combination of numerical value is stronger.What usual this method calculated
Small molecule is with protein affinity molecule at 1 ~ 1000 μM.By feldamycin in table 2 and DENV2-NS5 protein affinity numerical value 20
Between ~ 30 μM, illustrate that it has stronger binding ability with DENV2-NS5 albumen, it may be possible to the inhibitor of DENV2-NS5 albumen.
2 feldamycin of table and DENV2-NS5 protein affinity numerical tabulars
| KD（μM） | |
| Fidaxomicin | 23.4 |
Claims (4)
1. feldamycin is preparing the application in suppressing dengue virus medicine.
2. feldamycin is preparing relevant disease caused by treatment dengue virus infection and/or the application in the medicine of symptom.
3. application according to claim 1 or 2, it is characterised in that feldamycin is as dengue virus non-structural protein NS5
Inhibitor.
4. application according to claim 1 or 2, it is characterised in that the medicine includes pharmaceutically acceptable salt or load
Body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711009977.XA CN107929300B (en) | 2017-10-25 | 2017-10-25 | Application of fidaxomicin in preparation of medicine for treating relevant diseases and/or symptoms caused by dengue virus infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711009977.XA CN107929300B (en) | 2017-10-25 | 2017-10-25 | Application of fidaxomicin in preparation of medicine for treating relevant diseases and/or symptoms caused by dengue virus infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107929300A true CN107929300A (en) | 2018-04-20 |
| CN107929300B CN107929300B (en) | 2020-05-26 |
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|---|---|---|---|
| CN201711009977.XA Active CN107929300B (en) | 2017-10-25 | 2017-10-25 | Application of fidaxomicin in preparation of medicine for treating relevant diseases and/or symptoms caused by dengue virus infection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111939155A (en) * | 2020-08-03 | 2020-11-17 | 中山大学 | Application of indole alkaloid in preparation of anti-Zika virus and/or anti-dengue virus medicines |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016205009A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating infection by a platelet-targeting microbe using nanoparticles |
-
2017
- 2017-10-25 CN CN201711009977.XA patent/CN107929300B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016205009A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating infection by a platelet-targeting microbe using nanoparticles |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111939155A (en) * | 2020-08-03 | 2020-11-17 | 中山大学 | Application of indole alkaloid in preparation of anti-Zika virus and/or anti-dengue virus medicines |
| CN111939155B (en) * | 2020-08-03 | 2022-02-08 | 中山大学 | Application of indole alkaloid in preparation of anti-Zika virus and/or anti-dengue virus medicines |
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| Publication number | Publication date |
|---|---|
| CN107929300B (en) | 2020-05-26 |
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