CN107929300B - Application of fidaxomicin in preparation of medicine for treating relevant diseases and/or symptoms caused by dengue virus infection - Google Patents
Application of fidaxomicin in preparation of medicine for treating relevant diseases and/or symptoms caused by dengue virus infection Download PDFInfo
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- CN107929300B CN107929300B CN201711009977.XA CN201711009977A CN107929300B CN 107929300 B CN107929300 B CN 107929300B CN 201711009977 A CN201711009977 A CN 201711009977A CN 107929300 B CN107929300 B CN 107929300B
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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
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- 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
Abstract
The invention discloses application of fidaxomicin in preparing a medicine for treating related diseases and/or symptoms caused by dengue virus infection, the fidaxomicin is used as a medicine for resisting clostridium difficile infection which is clinically approved to be used, the safety is high, the fidaxomicin has high activity of inhibiting dengue virus, has stronger binding capacity with dengue virus non-structural protein NS5, and is expected to become a novel effective medicine for resisting dengue virus infection.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of fidaxomicin in preparing a medicine for treating related diseases and/or symptoms caused by dengue virus infection.
Background
Fidaxomicin (Fidaxomicin) (also known under the trade name Dificid, also known as dificicin, lipiarmycin, tiacumicin B, formerly known under the name PAR-101, OPT-80) is a bacterial DNA-dependent RNase inhibitor. Developed by Optimer for initial treatment of Clostridium Difficile Infection (CDI) and prevention of CDI recurrence, month 1 in 2011, the U.S. Food and Drug Administration (FDA) approved fidaxomicin for treatment of pediatric CDI, month 5 in 2011, the FDA approved fidaxomicin for adult CDI treatment.
Fidaxomicin has the following structure:
。
dengue virus belongs to flavivirus genus of Flaviviridae family, is RNA positive strand virus, and can cause symptoms such as systemic fever, eruption, arthritis and the like through mosquito transmission, and severe cases can cause shock death.
DENV-NS5 is an RNA-dependent RNA polymerase, which has the function of viral genome replication, plays an important role in viral replication, and can achieve the effect of killing dengue virus by inhibiting the activity of the enzyme.
Currently, there is a lack of clinically approved effective drugs against dengue virus.
Disclosure of Invention
The invention aims to provide the application of fidaxomicin in preparing a medicine for inhibiting dengue virus according to the defects in the prior art.
The technical purpose is realized by the following technical scheme:
the invention provides an application of fidaxomicin in preparing a medicine for inhibiting dengue virus.
Further, the fidaxomicin is applied to preparing the medicine for treating relevant diseases and/or symptoms caused by dengue virus infection.
Further, fidaxomicin acts as a dengue virus nonstructural protein NS5 (DENV-NS 5) inhibitor and inhibits dengue virus.
Further, fidaxomicin acts as an RNA-dependent RNase (DENV-NS 5 RdRp) inhibitor in DENV-NS 5.
The medicament also comprises a pharmaceutically acceptable salt or a carrier.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the fidaxomicin is used as a medicine for resisting clostridium difficile infection which is clinically approved to be used, has high safety, has high activity of inhibiting the dengue virus on a cellular level, has stronger binding capacity with DENV2-NS5 protein, and is expected to become a novel effective medicine for resisting the dengue virus infection.
Drawings
Figure 1 is that fidaxomicin inhibited expression of DENV2 prM protein in a549 cells.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, which are not intended to limit the invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
Example 1: inhibition of dengue virus (DENV) activity at cellular level by fidaxomicin
Virus strain: dengue virus DENV2 (NGC), cell line: a549
The detection method comprises the following steps:
fidaxomicin antiviral half Effective dose (50% Effective Concentration, EC)50): DMSO, 6, 9, 12, 18 and 24 mu M fidaxomicin saturates cells 1h in advance, and after 2h of virus infection, the virus-free culture medium containing the corresponding concentration of the drug is replaced to maintain for 48 h; cell supernatants were collected and tested for plaque formation inhibition by a plaque assay against solvent (DMSO) in various dose groups of fidaxomicin after viral infection.
Inhibition (%) = (1-number of viral plaque formed in administration group/number of plaque formed in solvent control group) 100%, and when inhibition equals 50%, the corresponding concentration of fidaxomicin was calculated using the Forcast equation of EXCEL2013, and used as EC50. Three replicates were averaged.
Inhibition of the cytotoxic half-cell activity of fidaxomicin (50% Cytotoxcitive Concentration, CC)50): adding a fidaxomicin gradient dose into A549 cell supernatant, maintaining for 48h, adding MTT, incubating for 4h, sucking out the culture medium, adding DMSO to detect absorbance value at 490nm, comparing with DMSO solvent control group, calculating inhibitor rate (%) = (1-dosing group 490nm absorbance value/solvent control group 490nm absorbance value) 100%, calculating by Forcast formula of EXCEL2013, and when the inhibition rate is 50%, determining the corresponding fidaxomicin concentration as CC50. Three replicates were averaged. Results are given in table 1:
table 1: fidaxomicin inhibits DENV EC in A549 cells50And CC50
| antiviral EC50（μM） | CC50（μM） | |
| DENV2（NGC） | A549 | |
| Fidaxomicin | 16.74±2.44 | 70.84±4.72 |
Example 2 inhibitory Activity of fidaxomicin on DENV2-prM protein in A549 cell line
Virus strain: dengue virus DENV2 (NGC)
Cell line: a549
The detection method comprises the following steps:
DMSO, 10, 50 and 100 mu M fidaxomicin saturates cells 1h in advance, and after 2h of virus infection, the virus-free culture medium containing the corresponding concentration of the drug is replaced to maintain for 48 h; cell pellets were collected, and the relative expression level of DENV2 (NGC) -prM protein in cells under different treatments was detected by Western blotting electrophoresis, and GAPDH was used as an internal reference protein. As shown in figure 1, fidaxomicin can effectively inhibit DENV membrane protein-DENV 2-prM protein under the concentration of 10-50 μ M, and the expression of DENV2-prM which is an important structural protein for constituting viruses is inhibited, which indicates that the reproduction of DENV2 is already inhibited.
Example 3 surface plasmon resonance detection of the affinity of fidaxomicin for DENV2-NS5 protein
The method adopts Biacore T100 instrument and CM5 chip of GE company to perform experiment, firstly, the purified DENV2 (NGC) -NS5 protein amino is coupled to the CM5 chip, and then flows throughFidaxomicin with different concentrations is detected by an instrument to detect the mass change of substances adsorbed on the surface of the chip, and the affinity rate (K) of the compound is calculateda) And dissociation rate (K)d). Affinity = dissociation equilibrium constant (K)D) The value describes the strength of binding between the small molecule and the protein molecule, the biological meaning being that when the small molecule binds to protein 1: 1 binding, the smaller the number, the stronger the binding, allowing a concentration of 50% small saturated protein molecules. Generally, the affinity molecules between the small molecules and the proteins calculated by the method are 1-1000 mu M. The affinity value of fidaxomicin and DENV2-NS5 protein in Table 2 is 20-30 mu M, which indicates that fidaxomicin has stronger binding capacity with DENV2-NS5 protein and is possibly an inhibitor of DENV2-NS5 protein.
TABLE 2 Furamycin affinity values for DENV2-NS5 protein
| KD（μM） | |
| Fidaxomicin | 23.4 |
Claims (3)
1. The application of fidaxomicin in preparing the medicine for inhibiting the dengue virus.
2. Use according to claim 1, characterized in that fidaxomicin acts as a dengue virus nonstructural protein NS5 inhibitor.
3. The use of claim 1, wherein the medicament comprises a pharmaceutically acceptable salt or carrier.
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| WO2016205009A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating infection by a platelet-targeting microbe using nanoparticles |
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| WO2016205009A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating infection by a platelet-targeting microbe using nanoparticles |
Non-Patent Citations (3)
| Title |
|---|
| Anilrudh A. Venugopal等.Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of Clostridium difficile Infection.《Clinical Infectious Diseases》.2012,第54卷(第4期),第568-574页. * |
| Ellie J. C. Goldstein等.Antimicrobial Activities of Fidaxomicin.《Clinical Infectious Diseases》.2012,第55卷第S143-S148页. * |
| 刘强强 等.登革病毒非结构蛋白NS5研究进展.《中国病毒病杂志》.2016,第6卷(第4期),第317-321页. * |
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