CN110075099B - Application of cyclohexene derivative in preparation of drug for resisting duck hepatitis virus type I - Google Patents

Application of cyclohexene derivative in preparation of drug for resisting duck hepatitis virus type I Download PDF

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CN110075099B
CN110075099B CN201910370777.XA CN201910370777A CN110075099B CN 110075099 B CN110075099 B CN 110075099B CN 201910370777 A CN201910370777 A CN 201910370777A CN 110075099 B CN110075099 B CN 110075099B
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duck hepatitis
cyclohexene derivative
cyclohexene
hepatitis virus
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CN110075099A (en
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马燕梅
陈吉龙
杨世丽
常巍
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Fujian Agriculture and Forestry University
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Abstract

The invention provides application of a cyclohexene derivative in preparation of a medicine for resisting duck hepatitis virus type I, wherein the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, the molecular formula of the cyclohexene derivative is C 15 H 17 ClFNO 4 S, the cyclohexene derivative is applied to preparation of a medicine for resisting duck hepatitis virus type I. Meanwhile, the invention discloses application of the cyclohexene derivative in preparation of a medicine for treating and/or preventing duck hepatitis, and provides more choices for clinical treatment of duck hepatitis.

Description

Application of cyclohexene derivative in preparation of medicine for resisting duck hepatitis virus type I
Technical Field
The invention relates to the field of biological medicines, in particular to application of a cyclohexene derivative in a drug for resisting duck hepatitis virus type I.
Background
The Duck Hepatitis Virus (DHV) mainly has three serotypes, namely DHV-I, DHV-II and DHV-III, and the three serotypes have no antigen correlation and no cross protection effect. Wherein, the I type duck hepatitis virus belongs to avian hepatitis virus of picornaviridae, is spherical or sphere-like, has a diameter of 20-40nm, has no cyst membrane and no blood coagulation, and can be proliferated in allantoic cavities of duck, chicken and goose embryos. The virus has strong resistance and can survive for a long time in the natural environment. The II type and III type duck hepatitis virus belong to astrovirus. The I type Duck Hepatitis Virus is distributed worldwide, can cause I type Duck viral Hepatitis (Duck Hepatitis Virus Disease type I, DVH-I), mainly attacks ducklings with the age of less than 3 weeks, is particularly easy to infect the ducklings with the age of less than 1 week, has the death rate of more than 90 percent, and is characterized in that the liver bleeds in a spotted manner and the ducklings died of illness are in an angle-bow-reversed posture when facing back. The type I duck hepatitis virus has great influence on China, and the type I duck viral hepatitis caused by the type I duck hepatitis virus is one of major infectious diseases harmful to duck breeding industry and is very unfavorable for the healthy development of duck breeding industry in China.
The main current prevention and treatment measure for duck hepatitis virus type I is immunization. At present, 3 immunization methods can make ducklings generate resistance to hepatitis A:
(1) the breeding duck is immunized, the offspring ducklings are guaranteed to obtain high-level passive immune antibodies, and the attenuated live vaccine of the I type duck hepatitis virus is widely applied at present.
(2) The duckling is directly subjected to active immunization by using the virus strain of the virus type I duck hepatitis which is subjected to the passage of the chick embryo.
(3) In the early stage of disease epidemic, the ducklings are injected with hyperimmune serum or recovered duck serum or egg yolk antibody urgently, so that infection can be prevented or fatality can be reduced.
In addition, the traditional Chinese medicine and the extracted components thereof are also reported to treat duck viral hepatitis, and the radix stephaniae tetrandrae is matched with antibiotics, the styrax is matched with the Pinctada yupingfeng powder by using Junchen, the Caoijing is matched with the capillary artemisia decoction for flavoring, the Chenhong tree is used for liver benefiting decoction, the Wang is used for Gentianhuang decoction, the Meng is used for tabasheer powder, and the Yinlong Erhuang decoction used for the Xiao Bao has better effect on treating duck viral hepatitis. In addition, because polysaccharide and flavonoid components have good antiviral activity, hongxu Du et al report that flavone polysaccharide, yixuan Wang et al report that astragalus polysaccharide, meiyun Song et al report that radix rehmanniae polysaccharide all have certain anti-duck hepatitis virus activity.
However, the vaccine has low immunization rate and certain limitation, and the hyperimmune serum or the yolk antibody has limited treatment effect on the sick ducklings, while the duck hepatitis virus has serious damage to the livers of the ducklings and high mortality rate after the disease attack. The application of the traditional Chinese medicine in the animal husbandry is restricted due to the reasons of large dosage, difficult quality control, relatively slow drug effect, poor palatability and the like.
Disclosure of Invention
The invention provides an application of a cyclohexene derivative in preparation of a medicine for resisting duck virus hepatitis type I, which can effectively solve the problems.
The invention is realized by the following steps:
application of cyclohexene derivative in preparation of medicine for resisting duck hepatitis virus type I, wherein the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, formula of cyclohexene derivative is C 15 H 17 ClFNO 4 S, the cyclohexene derivative is applied to preparation of a medicine for resisting duck hepatitis virus type I.
Application of cyclohexene derivative in preparation of medicine for treating duck hepatitis, wherein the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, formula of cyclohexene derivative is C 15 H 17 ClFNO 4 S, the application of the cyclohexene derivative in preparing a medicine for treating duck hepatitis.
Application of cyclohexene derivative in preparation of medicine for preventing duck hepatitis, wherein the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, formula of cyclohexene derivative is C 15 H 17 ClFNO 4 S, the application of the cyclohexene derivative in preparing a medicine for preventing duck hepatitis.
The beneficial effects of the invention are: the cyclohexene derivative can be effectively applied to duck hepatitis virus resistance, can be used for preparing medicines for treating and/or preventing duck hepatitis, and provides more choices for clinical treatment of duck hepatitis.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a comparison graph of the survival and death curves of ducklings before and after the infection of the duck hepatitis virus type I provided by the invention.
FIG. 2 is a picture of an HE stained strip of the liver of ducklings before and after infection with duck hepatitis virus type I.
FIG. 3 is a diagram of the change of the relative mRNA expression level of the type I duck hepatitis virus VP1 in the duckling liver detected by the PCR and qRT-PCR method provided by the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. Thus, the following detailed description of the embodiments of the present invention, as presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
In the description of the present invention, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or to imply that the number of technical features indicated is significant. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
The embodiment of the invention provides application of a cyclohexene derivative in preparation of a drug for resisting duck virus hepatitis, wherein the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate (ethyl (6R) -6- [ (2-chloro-4-fluorophenyl) sulfomethyl]cyclohexex-1-carboxylate), the cyclohexene derivative having the formula C 15 H 17 ClFNO 4 S is expressed by a structural formula (I) and is abbreviated as TAK242,
Figure BDA0002049864840000051
the cyclohexene derivative TAK242 is applied to preparation of the duck virus hepatitis resistant medicine. Specifically, the cyclohexene derivative TAK242 is used for preparing a duck hepatitis virus resistant medicament; the cyclohexene derivative TAK242 can also be used for preparing medicines for treating and/or preventing duck hepatitis. The duck hepatitis virus is duck hepatitis virus type I. The cyclohexene derivative TAK242 is used by intramuscular injection to ducklings infected with duck hepatitis virus.
After the cyclohexene derivative TAK242 is used for ducklings infected with I-type duck hepatitis viruses, the resistance of the ducklings to the I-type duck hepatitis viruses is enhanced, the survival rate of the ducklings is higher than that of ducklings infected with I-type duck hepatitis viruses without TAK242, liver damage caused by infection of the ducklings with the I-type duck hepatitis viruses can be effectively reduced, liver pathological changes are relieved, and virus carrying capacity is reduced.
The present invention will be described in more detail below by experimental verification through specific examples. In the present invention, materials, reagents, and the like used in examples are commercially available unless otherwise specified. In this example, the duck hepatitis virus type I strain is the chinese veterinary collection of microorganisms, accession number AV236; ethyl (6R) -6- [ (2-chloro-4-fluorophenyl) ] sulfamoyl cyclohexene-1-carboxylate as achievev Perfection, explorer the uknown, apex bio, USA, no. a3850; the ducklings for the test are cherry valley ducks, and are provided by Fuzhou Innovation farming and pasturing Co., ltd.
The invention verifies that the cyclohexene derivative TAK242 enhances the resistance of the duckling to the I-type duck hepatitis virus through the following steps.
1. Grouping and handling of test animals
60 SPF-grade 1-day-old ducklings are selected and randomly divided into 3 groups, namely a control group, a test I group and a test II group. Each group had 20. Wherein, the control group is a normal non-toxic group, the test I group is a duck hepatitis virus I infection-TAK 242 untreated group, and the test II group is a duck hepatitis virus I infection-TAK 242 treated group. Test IThe duckling is pre-treated for 2h by intramuscular injection of PBS, and then is injected with I type duck hepatitis virus (LD) 50 Is 10 -3.77 0.5 ml). Experiment II group of ducklings were pretreated with TAK242 (0.2 mg/duck) by intramuscular injection for 2 hours, and then injected with I type duck hepatitis virus (LD) 50 Is 10 -3.77 0.5 ml). And each group of ducklings are raised in the same environment.
The above 20 ducklings per group were carried out in 15 of the following steps 2 and in 5 of the groups in step 3.
2. Observe the influence of TAK242 on the survival rate of ducklings
And observing and recording the mental state, the morbidity and other conditions of each group of ducklings every day, recording the survival time of each group of ducklings, and drawing a survival and death curve. The ducklings of the control group all grew healthily in the test process and did not die. Referring to fig. 1, the ducklings in test group i began to die 24h after duck hepatitis virus infection, and the survival rates at 24h, 36h, 48h and 84h were 95.5%, 45.5%, 40.9% and 31.8%, respectively. The ducklings in the experiment II group begin to die 36h after the duck hepatitis virus infection, and the survival rates of the ducklings at 36h, 48h, 84h and 96h are 75.0%, 66.7% and 58.3% respectively. Through recording and comparing the survival time of the tested ducklings, the cyclohexene derivative TAK242 can prolong the survival time of the ducklings infected by the duck hepatitis viruses and has a protection effect on the ducklings.
Effect of TAK242 on the virulence of Duck hepatitis Virus
Taking a test duckling infected with duck hepatitis virus for 36h, killing the duckling by neck breaking, taking liver tissue, and detecting from two aspects of pathological section and virus load. For quantitative data, results were averaged over each group.
(1) Pathological section (HE staining) for observing pathological change degree of duckling liver
Collecting liver tissues of each group of ducklings, fixing the liver tissues in 4% paraformaldehyde, and carrying out preparation, observation and analysis on pathological sections. Referring to fig. 2, liver cords of the duckling livers of the control group are arranged regularly, and the hepatocyte structure is complete; the liver cord arrangement of the duckling livers in group I is disordered, part of liver cells are subjected to steatosis, part of liver cells are subjected to necrosis, cell nucleuses are fragmented, and a large number of red blood cells can be seen in liver parenchyma; and the ducklings in the experiment II group treated by TAK242 have lighter liver steatosis, less liver tissue structure damage and obviously lighter lesion degree than the attacking group.
(2) Determination of viral content in liver tissue
Under the conditions of asepsis and ice bath, the duckling is respectively subjected to a caesarean section for 24h and 36h, a liver sample is taken, and 50mg is weighed for nucleic acid extraction. And (3) carrying out reverse transcription on the extracted nucleic acid, and then detecting the content of the I-type duck hepatitis virus by using qRT-PCR. Referring to fig. 3, the duck hepatitis virus amount of the liver of the duckling in the test group ii treated with TAK242 was lower than that of the test group i in both 24h and 36h, and the difference was very significant. * Indicates that the difference was very significant (P < 0.01).
Through the experimental results of the above examples, it is known that the cyclohexene derivative TAK242 of the present invention can significantly reduce the pathogenic effect of the I type duck hepatitis virus on ducklings.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (3)

1. The application of the cyclohexene derivative in the preparation of the drug for resisting duck hepatitis virus type I is characterized in that the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, the molecular formula of the cyclohexene derivative is C 15 H 17 ClFNO 4 S, the cyclohexene derivative is applied to preparation of a drug for resisting duck hepatitis virus type I.
2. The application of the cyclohexene derivative in the preparation of the medicine for treating duck hepatitis is characterized in that the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, the molecular formula of the cyclohexene derivative is C 15 H 17 ClFNO 4 S, the application of the cyclohexene derivative in preparing a medicine for treating duck hepatitis, and the applicationDuck hepatitis is duck hepatitis caused by duck hepatitis virus type I.
3. The application of the cyclohexene derivative in the preparation of the medicine for preventing duck hepatitis is characterized in that the cyclohexene derivative is ethyl (6R) -6- [ (2-chloro-4-fluorophenyl)]Sulfamoyl cyclohexene-1-carboxylate, the molecular formula of the cyclohexene derivative is C 15 H 17 ClFNO 4 S, the application of the cyclohexene derivative in preparing a medicine for preventing duck hepatitis, wherein the duck hepatitis is duck hepatitis caused by duck hepatitis virus type I.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection;Shingo Oya,et al;《Am J Physiol Gastrointest Liver Physiol》;20131219;第G244页 *
TLR4 介导的鸭病毒性肝炎病毒诱导宿主天然免疫应答;马燕梅等;《福建省畜牧兽医学会2017年学术年会论文集》;20170922;第100页 *

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