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CN111166762A - Application of coenzyme A in preparation of medicine for treating or preventing avian influenza virus infection - Google Patents

Application of coenzyme A in preparation of medicine for treating or preventing avian influenza virus infection Download PDF

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CN111166762A
CN111166762A CN202010069054.9A CN202010069054A CN111166762A CN 111166762 A CN111166762 A CN 111166762A CN 202010069054 A CN202010069054 A CN 202010069054A CN 111166762 A CN111166762 A CN 111166762A
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coenzyme
influenza virus
avian influenza
infection
mice
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金梅林
张强
胡晓通
杨丽
王婷
孙小美
康超
钟鸣
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Huazhong Agricultural University
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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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

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Abstract

本发明涉及生物制剂领域，具体公开了辅酶A在制备治疗或预防禽流感病毒感染的药物中的应用。在致死性小鼠流感感染模型中，使用辅酶A治疗感染小鼠，可以有效改善小鼠体重下降、提高小鼠存活率，并且能够有效降低感染小鼠肺脏组织上清液中病毒滴度。因此，本发明公开的辅酶A是一种新发现的抗流感病毒的分子，可以用于开发预防或治疗流感病毒感染的药物，具有广阔的应用前景。The invention relates to the field of biological preparations, and specifically discloses the application of coenzyme A in preparing a medicine for treating or preventing avian influenza virus infection. In a lethal mouse influenza infection model, the use of coenzyme A to treat infected mice can effectively improve the weight loss of mice, improve the survival rate of mice, and effectively reduce the virus titer in the supernatant of the lung tissue of infected mice. Therefore, the coenzyme A disclosed in the present invention is a newly discovered anti-influenza virus molecule, which can be used to develop medicines for preventing or treating influenza virus infection, and has broad application prospects.

Description

Application of coenzyme A in preparation of medicine for treating or preventing avian influenza virus infection
Technical Field
The invention belongs to the technical field of biological medicines, and mainly relates to application of coenzyme A in preparation of a medicine for treating or preventing avian influenza virus infection.
Background
Influenza virus belongs to the genus influenza of the family orthomyxoviridae, a highly contagious disease worldwide, and the constant recurrence of viruses that threaten human health, worldwide, each annual influenza pandemic can infect approximately 10 million people, leading to three to five million serious diseases and up to one million deaths. The avian influenza virus belongs to the influenza virus A of the orthomyxoviridae, mainly occurs in poultry and wild poultry, and seriously hinders the development of poultry industry. Meanwhile, certain subtypes (H5, H7, H9 and H10) of the medicine can be spread to people across species, so that symptoms such as fever, cough, muscle ache, conjunctivitis, respiratory diseases and the like are caused, even death occurs seriously, and the medicine poses serious threat to human health.
Although avian influenza viruses have been mild and spread only between animals, cases of human infection with H7N9 were first discovered both in shanghai and anhui in 3 months in 2013, demonstrating the ability of this virus to transmit from birds to humans across interspecies isolation. H7N9 infected poultry hosts include chickens, ducks, geese, quails, etc., and wild hosts include waterfowls around rivers, lakes, and seas, as well as various migratory wild birds. The secretion, excretion or virus-contaminated environment of closely contacting infected birds can cause human infection with avian influenza virus H7N 9. According to the statistics of the World Health Organization (WHO), the number of people infected with H7N9 reaches 1564 in 3 months in 2018, wherein 1438 people are reported in China, 570 people die, and the disease death rate reaches 39.63%. Therefore, the prevention and control work of the avian influenza H7N9 is well done, so that the healthy development of the livestock and poultry breeding industry can be promoted, the social and economic stability can be effectively maintained, and the public health and safety can be guaranteed.
In the process of livestock and poultry breeding, the prevention and control technology for avian influenza at home and abroad mainly comprises the following steps: killing, disinfection, biological safety, vaccination and the like. Although the infected livestock and poultry can be killed to inhibit the spread of the avian influenza epidemic situation to a certain extent, the wild poultry serving as another important host of the avian influenza is difficult to control the avian influenza by killing, and meanwhile, the large-scale livestock and poultry killing can cause huge economic loss. Another effective measure for preventing the occurrence of avian influenza is vaccination, which can achieve an ideal protective effect when the vaccinated vaccine is identical to a clinically epidemic strain, but cannot provide effective immune protection when the vaccinated vaccine is different from the epidemic strain. The avian influenza viruses have a plurality of serotypes, and the mixed infection of the influenza A viruses with different subtypes often generates gene recombination to form new avian influenza viruses, thereby bringing great difficulty to the development and application of vaccines. Failure of immunity due to vaccination is often experienced in production practice as a result of the vaccine being vaccinated being different from the circulating strain.
Currently, the prevention measure for influenza virus infection is vaccination, and the treatment measures are mainly to use some neuraminidase inhibitors and ion channel M2 protein inhibitors, however, the effectiveness of these drugs is limited, and drug resistance may occur, and the wide antiviral resistance limits the clinical application of these inhibitors in preventing and treating influenza infection. Clinical and experimental evidence also suggests that prevention and treatment of influenza infection requires not only blocking viral transmission, but also reducing the inflammatory response of the viral infection to the host and damage to the lung epithelium, protecting epithelial cells from unwanted cell death. Therefore, in the course of preventing avian influenza, in addition to the development of drugs such as booster vaccines and inhibitors, other biological agents having a high anti-influenza effect should be actively developed.
Coenzyme A is a natural biochemical substance, is a macromolecule composed of pantothenic acid, adenine, ribonucleic acid, phosphoric acid and the like, widely exists in animal, plant and microbial tissues, has biochemical functions of providing organism capacity, providing active substances, transmitting acyl, activating immunity, promoting connective tissue formation and repair and the like, is mainly involved in the metabolism of fatty acid and pyruvic acid, and is an important factor for regulating the metabolism of sugar, fat and protein. Lijun (2012) researches find that the reserpine and coenzyme A have obvious curative effect in clinical application of treating leukopenia. However, Wangmuishi et al (2002) consider that the main component of coenzyme A, namely pantothenic acid, is not deficient in human body, coenzyme A does not need to be supplemented generally, and exogenous coenzyme A is a macromolecule and is difficult to enter cells through cell membranes, so that the curative effect of the coenzyme A is questionable.
However, in recent years, the role of coa in the treatment of diseases has attracted much attention in clinical practice, and oral coa precursors have been used in clinical treatments for obesity, hyperlipidemia, fatty liver, ischemic cardiomyopathy, and the like abroad, and more people in China have tried to treat diseases such as cytopenia, functional low fever, leukopenia, and the like with coa.
The coenzyme A has not been reported about the antiviral effect, particularly the anti-influenza virus effect, the invention reports that the coenzyme A has the anti-influenza virus effect for the first time, and the coenzyme A has better effect in preventing and treating the influenza virus.
Disclosure of Invention
The invention aims to solve the problem that influenza virus infection is difficult to prevent and treat, and provides application of coenzyme A in preparation of a medicine for treating or preventing avian influenza virus infection.
In order to achieve the purpose, the invention adopts the following technical measures:
the application of the coenzyme A in preparing the medicine for treating or preventing the infection of the avian influenza virus comprises the step of using the coenzyme A as the only effective component or one of the effective components for preparing the medicine for treating or preventing the infection of the avian influenza virus.
In the above applications, preferably, the coenzyme A is used for preparing an organism interferon stimulant after avian influenza virus infection;
or the application of the compound in preparing virus inhibitors after the infection of the avian influenza virus;
or for preparing an inhibitor of weight loss after avian influenza virus infection;
or for preparing a medicament for reducing the mortality rate after the infection of the avian influenza virus.
The avian influenza virus described above is preferably H7N 9;
the treatment mode of the medicine is injection.
Compared with the prior art, the invention has the following advantages:
(1) the coenzyme A in the invention can regulate the immune response of a host organism, increase the virus clearing capacity of the organism and reduce inflammatory injury caused by over-expression of cytokines.
(2) The injection of the coenzyme A can obviously improve the level of interferon of an organism, inhibit the proliferation of H7N9 influenza virus in a mouse body, improve the weight loss caused by H7N9 infection, improve the survival rate of the infected mouse and have obvious effect of resisting the H7N9 influenza virus infection.
Drawings
FIG. 1 is a graph showing the effect of coenzyme A on the body weight of H7N9 avian influenza virus-infected mice.
FIG. 2 is a graph showing the effect of coenzyme A on the survival rate of H7N9 avian influenza virus infected mice.
FIG. 3 is a graph showing the effect of coenzyme A on the content of H7N9 avian influenza virus in lung of mice infected with avian influenza virus.
FIG. 4 is a schematic diagram showing the effect of coenzyme A on H7N9 avian influenza virus-infected mouse lung cytokine.
Detailed Description
Unless otherwise specified, the test methods and conditions in the examples of the present invention are conventional methods. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples. The technical scheme of the invention is a conventional scheme in the field if no special description exists; the reagents or materials are commercially available, unless otherwise specified.
The invention takes avian influenza virus H7N9 as an example to illustrate the application of coenzyme A in the preparation of drugs for treating or preventing avian influenza virus infection, and because the level of interferon of organisms after being infected by avian influenza virus can be obviously improved after the coenzyme A is injected, the coenzyme A can also be used for treating or preventing other types of avian influenza virus infection. The following specific examples further illustrate the invention:
example 1:
effect of coenzyme a on body weight and survival rate of mice infected with avian influenza virus:
the test animals were 8 week old female C57BL/6 Specific Pathogen Free (SPF) mice, 20 in total, randomized into 2 groups of 10 animals each, all animals were housed in a biosafety tertiary laboratory (ABSL 3).
The first group was a 100ul intraperitoneal injection sterile PBS control group; the second group is a 100ul coenzyme A intraperitoneal injection test group.
Mice were injected intraperitoneally with PBS and coenzyme A solution every day for 3 consecutive days, and all mice were infected with 500 EIDs by nasal drip50H7N9 avian influenza virus, mice status was observed and body weight was measured for 15 consecutive days after influenza virus infection and survival was recorded.
Coenzyme A solution: coenzyme A is dissolved in sterile PBS to prepare 2mg/ml aqueous solution, and the daily administration dosage of the mice is 0.2 mg/mouse.
1. Effect of coenzyme A on body weight of H7N9 avian influenza Virus-infected mice
According to the results, in terms of body weight, the coenzymeA injected intraperitoneally can relieve the weight loss of mice caused by the infection of the H7N9 influenza virus, and particularly the improvement effect is most obvious in 6-10 days after the infection. (Table 1, FIG. 1).
TABLE 1 Effect of coenzyme A on mouse body weight following infection with H7N9 avian influenza Virus
Figure BDA0002376833670000041
Note: data without "±" indicates only 1 mouse left, and no standard deviation was calculated.
2. Effect of coenzyme A on survival rate of H7N9 avian influenza virus infected mice
The statistical result of the survival condition of the mice shows that the intraperitoneal injection of the coenzyme A can obviously improve the survival rate of the mice infected by the influenza virus to 50 percent compared with the PBS control group (the survival rate is 10 percent); the improvement is 40 percent compared with the PBS control group. (Table 2, FIG. 2).
TABLE 2 Effect of intraperitoneal coenzyme A on the survival of mice infected with H7N9 avian influenza Virus
Figure BDA0002376833670000042
Figure BDA0002376833670000051
Example 2:
the influence of coenzyme A on the lung virus titer and the cytokine content of mice infected by the avian influenza virus:
the test animals were 8 week old female C57BL/6 Specific Pathogen Free (SPF) mice, 20 in total, randomized into 2 groups of 10 animals each, all animals were housed in a biosafety tertiary laboratory (ABSL 3). The first group was a sterile PBS control group; the second group is the coenzyme a test group.
The coenzyme A solution and the injection dose were the same as in example 1.
Mice were injected daily with PBS or coenzyme A solution for 3 consecutive days, and all mice were infected with 500 EIDs by nasal drip50For H7N9 avian influenza virus, lung samples were taken from dissected mice at day 0 and day 5 post influenza virus infection, respectively, with 5 mice per group. The collected lung tissue samples were added with 1ml sterile PBS (1ml PBS/lung), homogenized and crushed by a homogenizer, centrifuged to take the supernatant, and frozen at-80 ℃ for detection of cytokine content and influenza virus content.
the cytokine to be detected includes TNF- α, IL-1 β, IFN-gamma, IFN- β, wherein the TNF- α, IL-1 β, IFN-gamma is administered using Magnetic
Figure BDA0002376833670000052
Assay multiplex kits(R&D Systems), IFN- β was detected using the VeriKine Mouse IFN- β enzyme-linked immunological assay kit (BioLegent) kit.
1. Effect of coenzyme A on Lung Virus content of H7N9 avian influenza Virus-infected mice
After mice are injected with coenzyme A in the abdominal cavity and infected with H7N9 influenza virus, the proliferation condition of the influenza virus in the lung is determined, and the result shows that the coenzyme A can remarkably reduce the proliferation of the influenza virus in the lung after the influenza virus infection (P is 0.0365), which indicates that the coenzyme A injected in the abdominal cavity can resist the infection of the influenza virus and has an antiviral effect (Table 3 and figure 3).
TABLE 3 Effect of coenzyme A on Lung Virus content (log) in mice infected with H7N9 avian influenza Virus10EID50/ml)
Grouping PBS control group Coenzyme A group
5 days after infection 5.468±0.218 4.946±0.411
2. Influence of coenzyme A on lung cytokine content of H7N9 avian influenza virus infected mouse
after coenzyme A is injected into the abdominal cavity and H7N9 influenza virus is infected, the content of cytokines in mouse lung tissue homogenate on the 0 th day after infection and the 5 th day after infection is measured, and the results show that the content of TNF- α, IL-1 β and IFN-gamma cytokines is obviously higher than that of a control group on the 0 th day after infection, the content of IL-1 β is obviously lower than that of the control group on the 5 th day after infection, and the content of IFN- β and IFN-gamma is obviously higher than that of the control group (Table 4 and figure 4).
The results show that the coenzyme A can improve the weight loss and the death rate of mice infected by H7N9, reduce the proliferation of influenza viruses in lung tissues, promote or inhibit the production of certain cytokines by regulating immune response to reduce inflammatory response, inhibit viruses by promoting the generation of body interferon, and has antiviral effect.
TABLE 4 Effect of coenzyme A on H7N9 avian influenza Virus infected mouse Lung cytokine content (pg/ml)
Figure BDA0002376833670000061

Claims (6)

1. Application of coenzyme A in preparing medicine for preventing and treating avian influenza virus infection is provided.
2. Coenzyme A is used for preparing an organism interferon stimulant after avian influenza virus infection.
3. Application of coenzyme A in preparation of virus inhibitor after avian influenza virus infection.
4. Application of coenzyme A in preparation of inhibitor for weight loss after avian influenza virus infection is provided.
5. Application of coenzyme A in preparation of medicines for reducing mortality rate after avian influenza virus infection.
6. The avian influenza virus of any of claims 1 to 5 which is H7N 9.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119633011A (en) * 2024-12-27 2025-03-18 深圳北京中医药大学研究院 Application of acetyl coenzyme A in preparing medicine for treating pneumonia

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CN1302892A (en) * 1999-10-28 2001-07-11 上海博容基因开发有限公司 Polypeptide-human chondriosome acyl-CoA thioesterase 48 and polynucleotide for coding it
CN1370550A (en) * 2001-02-23 2002-09-25 田维熙 Fatty acid synthetase inhibitor and its prepn and application
CN1883705A (en) * 2006-05-19 2006-12-27 华扩达动物科技(I.P.5)有限公司 Application of Cysteamine and Its Derivatives in Preparation of Drugs for Improving Avian Influenza Vaccine Antibody Titer
CN106974920A (en) * 2017-01-02 2017-07-25 胡友忠 Whole process is without vaccine livestock and poultry medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1302892A (en) * 1999-10-28 2001-07-11 上海博容基因开发有限公司 Polypeptide-human chondriosome acyl-CoA thioesterase 48 and polynucleotide for coding it
CN1370550A (en) * 2001-02-23 2002-09-25 田维熙 Fatty acid synthetase inhibitor and its prepn and application
CN1883705A (en) * 2006-05-19 2006-12-27 华扩达动物科技(I.P.5)有限公司 Application of Cysteamine and Its Derivatives in Preparation of Drugs for Improving Avian Influenza Vaccine Antibody Titer
CN106974920A (en) * 2017-01-02 2017-07-25 胡友忠 Whole process is without vaccine livestock and poultry medicine

Non-Patent Citations (2)

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Title
L A PAIGE ET AL.: "S-(2-Oxopentadecyl)-CoA, a Nonhydrolyzable Analogue of Myristoyl-CoA, Is a Potent Inhibitor of Myristoyl-CoArProtein ZV-Myristoyltransferase", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
黄佳昭等: "酰基辅酶A 结合结构域蛋白3 在病原微生物复制中的作用", 《生物化学与生物物理进展》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119633011A (en) * 2024-12-27 2025-03-18 深圳北京中医药大学研究院 Application of acetyl coenzyme A in preparing medicine for treating pneumonia

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Application publication date: 20200519