CN110292576A - Application of the rotigotine in the drug that preparation treats or prevents influenza infection - Google Patents
Application of the rotigotine in the drug that preparation treats or prevents influenza infection Download PDFInfo
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Abstract
The invention discloses application of the rotigotine (Rotigotine) in preparation prevention or treatment influenza infection drug.Applicant has detected rotigotine to the toxicity of cell on person monocytic cell's U937 model, and the anti-influenza virus activity of rotigotine is determined within the scope of non-toxic concentrations.The results show that this small molecule compound has significant antiviral activity, and it selects index to be greater than 76.In addition, rotigotine also has significant antiviral activity, and antivirus action is in dose-dependent effect on human squamous lung cancer system A549 and canine kidney cells system MDCK.In Antiviral Effect wide spectrum Journal of Sex Research, rotigotine can a variety of influenza virus sub-strains of the dose-dependent inhibition including Oseltamivir drug resistance H1N1 strain, H3N2 strain and IBV.Therefore, the rotigotine of present disclosure is a kind of novel anti-influenza virus medicament, have good safety, selection index height and have many advantages, such as broad anti-viral activity, can be used for developing prevention or treat the drug of influenza infection, has broad application prospects.
Description
Technical field
The invention belongs to pharmaceutical technology fields, relate generally to rotigotine in preparation and treat or prevent influenza infection
Application background technology in drug
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.According to virion daughter nucleus egg
The difference of the antigenic characteristic and genetic characteristics of white (NP) and stromatin (M), influenza virus are divided into tri- type of A, B, C, also referred to as first,
Second, the third three types.The sub-thread strand RNA that influenza A full-length genome is differed in size by 8 forms, respectively with segment 1 to segment
8 names.Full length viral genome about 13.6kb encodes 10 kinds of structural proteins (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-
F2 and NS2/NEP) and non-structural protein (NS1).According to virion surface glycoprotein hemagglutinin (HA) and neuraminidase
(NA) difference, influenza A can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotypes.Human influenza virus
Mainly H1, H2 and H3 hypotype.And endangering serious highly pathogenic bird flu at present is mostly H5, H7 and H9 hypotype, wherein with
H5N1 hypotype lethality highest.Type B influenza virus often causes influenza localized epidemics, does not cause worldwide influenza great outburst, only exists
It is found in people and sea dog.C-type influenza virus exists mostly in the form of being dispersed in, and primary attack infant does not cause influenza pandemic generally,
The mankind and pig can be infected.
Influenza virus has caused to be very popular for five times in the world since early 20th century finds, can generate within 10 years or so
Outbreak of epidemic, causes huge loss in the world.Influenza pandemic can lead 250,000~500,000 death every year,
3000000~5,000,000 grave illness examples, the people that the whole world about shares 5~15% are infected.Currently, the therapeutic strategy master of confrontation influenza infection
It wants that antiviral therapy and two kinds of anti inflammatory immunity opsonic therapy can be divided into.Antiviral therapy controls the primary method of influenza pandemic, and
And be very popular break out when as main prevention and treatment drug play central role.So far, only two classes are antiviral
Drug is ratified by the whole world and can be used for treating influenza infection, is influenza m 2 ion channel blocking agents and influenza virus mind respectively
Through propylhomoserin enzyme (NA) inhibitor.Although M2 retarding agent had good antiviral effect in the past, with Drug resistance strain
Continuously emerge, the World Health Organization in 2009 by amantadine and Rimantadine from the Tamiflu for recommending clinical use
It is excluded in inventory.Therefore, NA inhibitor is unique influenza virus drug that current WHO recommends.Neuraminidase inhibitor
Representative is oseltamivir and Zha La meter Wei, and such drug is equal to all known human influenza virus and highly pathogenic avian influenza virus
Effectively.But the persister of oseltamivir continuously emerges in recent years, therefore, studying and developing novel anti-influenza virus medicament has weight
Want meaning.
Rotigotine is a kind of dopamine-receptor stimulant of non-ergot woods class, can non-selective activation include D1-
A variety of dopamine receptors including D5 receptor.The medicine found that rotigotine patch agent in 2007 is eaten by the U.S. in 1985 for the first time
Product and Drug Administration (FDA) are approved as the skin-penetrating therapeutic drug of first, U.S. Parkinson's disease.In August, 2008, rotigotine
It is authorized to for treating restless leg syndrome.Currently, the drug has obtained the approval in Europe, the Middle East and African Territories, for controlling
Treat Parkinson's disease and restless leg syndrome.Up to the present, the relevant report in relation to rotigotine resisiting influenza virus is not found.
Summary of the invention
It is an object of the invention to make up the deficiencies in the prior art, provides a kind of small molecule compound rotigotine and making
The standby application treated or prevented in influenza infection drug, so that the treatment for clinically influenza provides one kind safely and effectively
Small molecule compound.Rotigotine can effectively inhibit the duplication of influenza virus in non-toxic range, can further develop
For the drug for treating or preventing influenza infection disease, it is with a wide range of applications.The English of rotigotine is entitled
Rotigotine has structure shown in structural formula I:
In order to achieve the above purpose, the technical solution adopted by the present invention is that:
Rotigotine treats or prevents the application in influenza infection drug in preparation:
1 evaluates toxicity, the antiviral activity of rotigotine in U937 influenza infection model, and calculates it and select index,
Its step are as follows:
(1) human monocyte cell line U937 is spread with proper density into 96 orifice plates, to detect antiviral effect, then simultaneously
Infect the influenza virus (A/PuertoRico/8/34 (H1N1)) of suitable concentration.
(2) rotigotine that addition simultaneously is diluted to various concentration gradient with culture medium cultivates 48h into above-mentioned hole.
(3) cell viability of drug-treated group and untreated fish group is detected, to detect the cytotoxicity of rotigotine.
(4) detection drug-treated group and influenza neuraminidase activity in untreated fish group supernatant, to assess sieve for dagger-axe
Spit of fland antiviral activity.
(5) antiviral selection index of the rotigotine on U937 is calculated.
2 evaluate the toxicity and antiviral effect of rotigotine in different cell lines, and its step are as follows:
(1) human squamous lung cancer system A549 and canine kidney cells system MDCK are spread with proper density into 96 orifice plates, with suitable
Density is spread into 96 orifice plates, cultivates 18-24h.After it grows up to single layer, addition is diluted to sieve of various concentration gradient with culture medium
For dagger-axe spit of fland, 48h is cultivated, to detect drug toxicity.
(2) if detection antiviral effect, by above-mentioned cell monolayer with debita spissitudo influenza virus infection (A/
PuertoRico/8/34 (H1N1)) and the rotigotine of various concentration gradient is added, cultivate 48h.
(3) cell viability of drug-treated group and untreated fish group is detected, to detect the cytotoxicity of rotigotine.
(4) detection drug-treated group and influenza neuraminidase activity in untreated fish group supernatant, to assess sieve for dagger-axe
Spit of fland antiviral activity.
(5) selection index of the rotigotine in two kinds of cell lines is calculated.
The broad spectrum activity of 3 rotigotine antiviral effects is analyzed
(1) A549 cell or mdck cell are spread with proper density into 96 orifice plates, 18- is cultivated in cell incubator
For 24 hours and after growing up to single layer, using including H1N1 Oseltamivir persister (A/PuertoRico/8/1934H274Y), H3N2 hypotype
(A/Human/Hubei/3/2005) the different influenzas poison and including influenza B virus (B/Human/Hubei/1/2007)
Strain infection cell, infection titer is 1MOI (infection multiplicity), while the drug of various concentration gradient is added, and cultivates 48h.
(2) detection drug-treated group and influenza neuraminidase activity in untreated fish group supernatant, it is anti-to assess drug
Virus wide spectrum.
(3) rotigotine is calculated to the half-inhibitory concentration (IC of above-mentioned three kinds of influenza viruses50)。
The influenza virus includes but is not limited to: Influenza virus H1N1 hypotype (A/PuertoRico/8/1934),
H1N1 Oseltamivir persister (A/PuertoRico/8/1934H274Y), H3N2 hypotype (A/Human/Hubei/3/2005) with
And influenza B virus (B/Human/Hubei/1/2007).
Protection scope of the present invention further include:
Rotigotine is in the external application inhibited in influenza virus duplication drug of preparation；
Rotigotine treats or prevents the application in influenza infection drug in preparation as sole active ingredient；
Compared with prior art, the present invention having the following advantages that and effect:
1 rotigotine is small molecule compound, the CC in source of people U937 and A549 cell50(half lethal concentration) is big
In 150 μM.Its duplication for capableing of dose-dependent inhibition H1N1PR8 influenza virus in different cell lines is thin in U937
IC in born of the same parents system and A549 cell line50(half-inhibitory concentration) is only 2.1 μM.By calculating, the selection index of rotigotine
(SI) it is about 76.7 on U937, is about 92.9 on A549 cell, it is safe and efficient to illustrate that it has the characteristics that.
2 rotigotines being capable of dose-dependent inhibition Flu-A H1N1 hypotype, H3N2 hypotype and influenza B virus IBV
Duplication has good broad anti-viral activity.In addition, rotigotine can also effectively inhibit the medicament-resistant mutation for Oseltamivir
Strain, this makes rotigotine have very big clinical treatment potentiality and wide application prospect.
3 rotigotines have a large amount of clinical laboratory data in listing many years, good security, if being made
For treatment of influenza medication, clinical testing times can be significantly reduced, save great amount of cost.
Detailed description of the invention
Toxicity of Fig. 1 rotigotine in U937, antiviral effect
A is U937 cell viability after various concentration drug-treated in Fig. 1；
In Fig. 1 B be various concentration drug on U937 to the inhibiting rate of H1N1 influenza virus；
Toxicity and antiviral effect of Fig. 2 rotigotine in A549 and MDCK
A is A549 cell viability after various concentration drug-treated in Fig. 2；
In Fig. 2 B be various concentration drug on A549 to the inhibiting rate of H1N1 influenza virus；
C is mdck cell vigor after various concentration drug-treated in Fig. 2；
In Fig. 2 D be various concentration drug on MDCK to the inhibiting rate of H1N1 influenza virus.
The detection of Fig. 3 rotigotine broad anti-viral activity
A is after various concentration drug-treated to the inhibiting rate of Flu-A H1N1 Oseltamivir persister in Fig. 3；
B is after various concentration drug-treated to the inhibiting rate of Flu-A H3N2 hypotype in Fig. 3；
C is after various concentration drug-treated to the inhibiting rate of influenza B IBV in Fig. 3.
Specific embodiment
In order to better understand the content of the present invention, the content of present invention is made furtherly below with reference to specific implementation method
Bright but of the invention protection content is not limited to following embodiment.Technical solution of the present invention is if not otherwise specified
Routine techniques；Agents useful for same or material derive from commercial channel if not otherwise specified.
Currently, anti-influenza virus medicament evaluation model is broadly divided into external model (in vitro model) and In vivo model
(in vivo model).External model mainly uses various influenza sensitive cell lines or influenza pathology relevant cell system to drug
It is evaluated, the advantage is that can provide the identical cell of a large amount of inhereditary features is research object, it is easy to operate, it can eliminate other
The influence of extraneous factor, and can detecte drug toxicity, effective concentration and selection indexes Index, it is provided more for later period mechanism study
It is mostly basic.The present invention uses three kinds of cell models, carries out quantitative analysis to the external anti-influenza activity of rotigotine.It utilizes simultaneously
The Influenza virus strain of different subtype has detected the antiviral broad spectrum activity of rotigotine.
Experimental material:
(1) cell line needed for testing and virus
U937, A549 and mdck cell are purchased from American Type Culture Collecti (ATCC)；
Strain used: Influenza virus H1N1 hypotype (A/PuertoRico/8/1934), H1N1 Oseltamivir persister
(A/PuertoRico/8/1934H274Y), H3N2 hypotype (A/Human/Hubei/3/2005) and influenza B virus (B/
Human/Hubei/1/2007)。
(2) drug needed for testing
Rotigotine is purchased from Shanghai MCE company；When cell experiment, drug is dissolved with DMSO.
(3) reagent needed for testing:
RPMI-1640 culture medium, fetal calf serum (FBS) are purchased from GIBCO company；
4-methylumbelliferyl- α-N-acetyl-neuraminate (MUNANA) is purchased from Sigma；
MTS cell proliferation detecting kit is purchased from Promega company；
(4) instrument needed for testing:
EnSpire multi-function microplate reader is purchased from PerkinElmer company；
CO2 cell incubator is purchased from Thermo company.
Embodiment 1: antiviral activity evaluation of the rotigotine in U937 cell line
1 cell culture
Cell after taking cryopreservation resuscitation after 2 passages, with containing 10% fetal calf serum and it is dual anti-(penicillin 100U/ml,
Streptomysin 100ug/ml) RPMI-1640 culture medium spread cultivation, inoculum density be not less than 5x105Cell/ml, passage density is not high
In 2x106cell/ml。
The cytotoxicity of 2 rotigotines detects
U937 cell presses 1.5 × 105Cells/well (100 μ L of volume) is inoculated in 96 porocyte culture plates；With every 100 μ of hole
L liquid medium (+10% serum of RPMI-1640 culture medium+dual anti-) compounding pharmaceutical, and be added in corresponding cell hole and mix.Drug
8 concentration are set, are originated from 400 μM, 2 times of gradient dilutions are to 3.125 μM.After cultivating 48h, 500 × g of tissue culture plate centrifugation
3min abandons supernatant.It is added the serum-free RPMI-1640 culture medium 100 μ L containing 20%MTS reagent into remaining cell, 37 DEG C
It is incubated for 1h, 500 × g is read after being centrifuged 3min with EnSpire microplate reader detection OD 490, calculates cell survival rate.
Cell viability (%)=drug-treated group/untreated control group × 100%
As a result as shown in figure 1 shown in A, after the rotigotine processing U937 cell 48h of various concentration, half toxic concentration
CC50About 160.7 μM.
Antiviral activity of 3 rotigotines to influenza A virus strain A/PuertoRico/8/34 (H1N1)
3.1 experimental principles: MUNANA (4-methylumbelliferyl- α-N-acetyl-neuraminate) is influenza
The specific substrate of neuraminidase, the catalysate generated under neuraminic acid enzyme effect are irradiated in 355nm exciting light
Under, it can produce 460nm fluorescence, the number of neuraminidase expression quantity represented, training is reflected for the power of fluorescence intensity
Support the virus quantity in cell conditioned medium.
U937 cell is pressed 1.5 × 10 by 3.25Cells/well (100 μ L of volume) is inoculated in 96 porocyte culture plates, infection
The H1N1PR8 virus of 0.1MOI, while the culture solution that the drug that each gradient concentration is added is 200 μ L to total volume is added in group
(+10% serum of RPMI-1640 culture medium+dual anti-) takes each experimental port supernatant to carry out in cell incubator after 37 DEG C of culture 48h
The detection of neuraminidase expression quantity.
3.3 are added 20 μ L buffer (32.5mM MES, pH 6.5,4mM in the opaque 96 hole micro plate of black matrix
CaCl2) 20 μM of MUNANA of substrate prepared add each 40 μ L of experimental port culture supernatant, and 37 DEG C are protected from light incubation 60min, are added
100 hole μ L/ of reaction terminating liquid (0.014 μM of NaOH, 83% ethyl alcohol) measures fluorescent value (excitation wavelength on micropore plate reader
355nm, wavelength of transmitted light 465nm).
3.4 calculate the inhibiting rate of drug infected by influenza duplication in each detection hole
Inhibiting rate (%)=100- (drug-treated hole-blank control)/(virus control wells-blank control) × 100%
As a result as shown in figure 1 shown in B, rotigotine significantly suppresses influenza virus duplication, and is in dose-dependence,
Half-inhibitory concentration IC50About 2.1 μM.
3.5 medicament selection indexes calculate
Medicament selection index (SI) is used to judge the safe range of effect of drugs, and selecting index to be greater than 1.00, the above are have
Effect, index is bigger, and safe range is bigger.Its calculation formula is: SI=CC50/EC50
In conjunction with above-mentioned data, rotigotine index that selects of resisiting influenza virus on U937 is 76.7, is belonged to safe and efficient
Anti-influenza virus medicament.
Embodiment 2: the evaluation of anti-influenza virus activity of the rotigotine in A549 and mdck cell system
This experiment in source of people pulmonary epithelial cells A549 and canine kidney cells MDCK, is commented using the method for similar embodiment 1
The antiviral effect of valence rotigotine.
Since A549 and MDCK is attached cell, when detecting drug toxicity and antiviral activity, the institute in 96 orifice plates
Needing cell number is 1.5 × 104Cells/well, and 24 hours in advance paving cells are needed, liquid is changed before infection, remaining operation and implementation
Example 1 is consistent.
1 drug toxicity
As a result as shown in A and C in Fig. 2, after the drug-treated cell 48h of various concentration, cell viability is detected.As a result table
It is bright, half toxic concentration CC of the rotigotine on A54950It is 195.1 μM, and on mdck cell, the CC of rotigotine50About
It is 93.1 μM.
2 antiviral activities
As a result as shown in the B and D in Fig. 2, rotigotine obviously inhibits influenza virus to replicate, and closes in dose-dependant
System, the medium effective concentration IC of suppressing virus replication in A549 cell50About 2.1 μM, the IC in mdck cell50About
It is 18 μM.
3 medicament selection indexes calculate
In conjunction with above-mentioned data, rotigotine selection index of resisiting influenza virus on A549 is about 93, on mdck cell
Selection index be about 5.2.Rotigotine is significantly higher than it on dog source cell in the antiviral activity that human archeocyte is fastened
Activity prompts rotigotine that may play more preferable effect in Human Influenza infects, and its antiviral activity may pass through the mankind
Host's target is realized.
Embodiment 3: the broad spectrum activity analysis of rotigotine antiviral effect
It includes H1N1 Oseltamivir persister (A/PuertoRico/8/1934H274Y), H3N2 hypotype that the present embodiment, which is used,
(A/Human/Hubei/3/2005) and three kinds including influenza B virus (B/Human/Hubei/1/2007) not cocurrent flows
Influenza Virus hypotype infects A549 or mdck cell system, the same Examples 1 and 2 of method respectively.
As shown in figures 3 a-c, rotigotine obviously inhibits the duplication of three kinds of different influenza subtypes, and is in dose-dependant
Relationship, to the IC of H1N1 Oseltamivir persister50It is 8.83 μM, to the IC of H3N2 hypotype50It is 28.9 μM, to influenza B
The IC of strain IBV50It is 7.95 μM.
Above-mentioned data explanation, rotigotine present good broad-spectrum antiviral characteristic in cellular level, can be effectively suppressed
The duplication of different influenza subtypes.Meanwhile for the Oseltamivir drug resistance strain H1N1H274Y occurred at present, rotigotine also can
Effectively inhibit, illustrates that it has good clinical treatment potentiality and wide application prospect for influenza drug resistance strain.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to
The limitation present invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should all include
Within protection scope of the present invention.
Claims (5)
1. application of the rotigotine in the drug that preparation treats or prevents influenza infection.
2. application as described in claim 1, it is characterised in that: the influenza virus is influenza A virus and influenza B
Virus.
3. application as described in claim 1, it is characterised in that: any one is made as active pharmaceutical ingredient in rotigotine
Pharmaceutically acceptable dosage form.
4. application according to claim 3, it is characterised in that: the dosage form be tablet, capsule, granule, oral solution,
Injection.
5. application according to claim 2, the influenza virus is Influenza virus H1N1 hypotype (A/
PuertoRico/8/1934), H1N1 Oseltamivir persister (A/PuertoRico/8/1934H274Y), H3N2 hypotype (A/
) and influenza B virus (B/Human/Hubei/1/2007) Human/Hubei/3/2005.
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| CN107108683A (en) * | 2014-10-31 | 2017-08-29 | 共晶制药股份有限公司 | 2 ' for treating flaviviridae and cancer, 2 ' dihalo nucleoside analogs |
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| US20110027345A1 (en) * | 2007-07-06 | 2011-02-03 | Shuming Wang | Composition containing rotigotine and use thereof and transdermal patch containing the composition |
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Application publication date: 20191001 |
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