CN100577179C - Application of chitin, chitosan and their derivatives in preparing antivirotic - Google Patents
Application of chitin, chitosan and their derivatives in preparing antivirotic Download PDFInfo
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- CN100577179C CN100577179C CN03128740A CN03128740A CN100577179C CN 100577179 C CN100577179 C CN 100577179C CN 03128740 A CN03128740 A CN 03128740A CN 03128740 A CN03128740 A CN 03128740A CN 100577179 C CN100577179 C CN 100577179C
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Classifications
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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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention is the application of chitin, chitosan and heir derivatives in preparing antiviral preparation. Extraneous antiviral experiment, animal experiment and histopathological examination show that chitin, chitosan and heir derivatives has wide spectrum antiviral activity on RNA virus, DNA virus and retrovirus, excellent effect of preventing and treating viral diseases and no toxic side effect. Therefore, chitin, chitosan and heir derivatives may be prepared into antiviral preparation or disinfectant.
Description
Technical field
The present invention relates to the antiviral activity of chitin and chitosan and derivant thereof, more particularly, relate to the application in the preparation antiviral agent of chitin and chitosan and derivant thereof.
Background technology
A lot of torment human important infectious disease and cause, the popular uneasiness that more and more causes people of the disease that causes by one or more viruses by virus.Why important some infectious disease by because they often are fatal; These infectious disease are that rabies, variola, spinal cord friend matter inflammation, hepatitis, yellow fever, immunity are picked out and decreased and multiple encephalitis.Other infectious disease also important reasons is that they have infectiousness, and acute discomfort can occur, as influenza, and measles, parotitis and chickenpox, and respiratory tract one gastrointestinal upset.Other infectious disease and cytomegalovirus as rubella can cause birth defect, and oncovirus can cause the tumor and the cancer of humans and animals.And cause SARS (Severe Acute Respiratory Syndrome SARS (Severe Acute Respiratory Syndrome) the is commonly called as atypical pneumonia) whole world popular at present then is SARS virus---the mutation of coronavirus.
The virus of coronaviridae only infects vertebrates, and is relevant with the numerous disease of humans and animals.This viroid has gastrointestinal tract, respiratory tract and neural preferendum.Known " coronavirus " kind surpasses 20, and 9 groups of genes are arranged, and can be present on one's body cattle, horse, Canis familiaris L. and the avian, and relevant with the mankind has 3 kinds.Its representative strains is avian infectious bronchitis virus, other member has human corona virus, murine hepatitis virus, pigs haemagglutinating encephalomyelitis virus, transmissible gastro-enteritis virus, nascent calf diarrhoea coronavirus, rat coronavirus, turkey blue comb poison, feline infectious peritonitis virus, and possible member has canine coronavirus, rat saliva order adenitis virus, people's enteric coronavirus virus.The human corona virus belongs to OC43 and two antigenic types of 229E respectively, and it is the cause of disease that causes human upper respiratory tract infection, and typical coronavirus infection is cold symptoms such as watery nasal discharge, discomfort.The pathogenicity difference of different type viruses, the clinical manifestation that causes also is not quite similar, and the symptom that the CC43 strain causes is generally serious than 229E virus.Coronavirus is one of main pathogen of adult's common cold, and child's coronavirus infection is but uncommon.But the child had 50% can detect neutralizing antibody in 5～9 years old, the 70% neutralizing antibody positive among the adult.Coronavirus also is the important cause of disease that adult's chronic tracheitis patients acuity increases the weight of.But cause the coronavirus of this severe acute respiratory syndrome, its gene structure and existing 3 kinds of viruses are different, be likely the variation kind that causes the common cold coronavirus, or, infect to the people as bird flu because virus breaks through people and animal The Natural Divisions.World Health Organization (WHO) is at official confirmation on April 16th, 2003, and the pathogen that causes atypical pneumonia is the mutation of coronavirus, does not find at human body in the past.The member of coronavirus family generally has 29,000 to 31,000 nucleoside, and the gene ordering of SARS virus has 29,727 nucleoside, within the typical ribonucleic acid dividing value of coronavirus.
SARS virus is that a kind of normal chain has film ribonucleic acid (RNA) virus, is easy to morph.It is reported, Hong Kong University's medical college department of microbiology compares a plurality of atypical pneumonia virus samples from Hong Kong, Guangzhou and ground such as the U.S., Canada, unexpectedly find central 6 Virus Samples, combination inequality appears in a certain fragment gene, this find with some atypical pneumonia patient infections after the state of an illness phenomenon such as very big difference occurs and match.In fact, although World Health Organization (WHO) announces that the mutation of coronavirus is the SARS arch-criminal, some scientists think that till now, the pathogen of SARS is not found out fully.
The treatment of atypical pneumonia, general critically ill patient can use medicament for immunity enhancement, as thymosin, gamma globulin and interferon etc.It is generally acknowledged that interferon can make cell swash in advance, makes it fully to show when viral infection antiviral state, to reach prevention infection, mitigation symptoms, reduction sickness rate, to reduce the effect that virus is discharged.Interferon is as being that a kind of cell is regulated albumen, it with the receptors bind of human cell surface after, can irritation cell produce multiple antiviral protein and come kill virus, and have the effect of raising immunity.Interferon all has inhibitory action to present known most viruses, be the medicine with antiviral activity of generally acknowledging in the world at present, be widely used in many viral diseases such as treatment chronic type b, hepatitis C, pneumonia, epidemic hemorrhagic fever, viral meningitis, condyloma acuminatum, herpes.Recently, the American Studies personnel are testing the new drug of a kind of employing " antisense therapy " trial-production, and this new drug contains the rna single strand symmetrical with the SARS coronavirus sequence in the gene, the toxicity of the virus that can thoroughly neutralize.As this, this new drug it is said can effectively attack ribonucleic acid (RNA) the gene strand of infectious hepatitis virus, west Nile virus and SARS coronavirus etc., stop the procreation process of duplicating of SARS coronavirus gene, thereby reach the purpose that stops disease to take place and worsen.A lot of Chinese herbal medicine such as Flos Lonicerae, Radix Isatidis etc. and Chinese medicine compound have been brought into play very big effect in preventing and treating atypical pneumonia, but definite curative effect needs further research and confirms.
The carapace rope (Chitin) claim chitin, chitin, chitosan, chitin, acetylglucosamine etc. again, chemical name is poly-n-acetyl-D-glucamine, it is a kind of natural biological macromolecular compound, extensively be present in the carapaces such as shrimp, Eriocheir sinensis, the billions of tons of the annual biosynthetic carapace Suo Keda of nature are a kind of ten minutes rich natural resource.Owing to contain multiple functional group in the carapace Cable Structure; therefore; have very strong reactivity, reactions such as deacetylation, hydrolysis, crosslinked, grafting, acidylate, etherificate, carboxy methylation, oxidoreduction and complexation can take place, generate chitin derivativ with different performance.Wherein be called chitosan (Chitosan) behind the chitin deacetylate, claim chitosan, soluble chitin etc. again, chemical name is (1,4)-2-amino-2-deoxidation-callose.Chitosan contains free amine group, and reactivity and solubility property are all strong than chitin.Chitin and chitosan have stronger biological activity because of its special construction, existing known have blood fat reducing, blood pressure lowering, blood sugar lowering, enhancing immunity, antibiotic effect such as anticancer.Studies show that up to now, chitin and chitosan and derivant thereof do not see that human body is had obvious toxic and side effects.(Materials Science and Engineering such as Zheng Lianying, 2000,18 (2): 22) report, in the scope of molecular weight below 30.5 ten thousand, with the increase of chitosan concentration, the effect of its antibacterial action strengthens, when concentration is 1.0%, to gram positive bacteria with to gram negative bacteria, its antibiotic rate all reaches 100%; To the Gram-positive mattress, with the molecular weight increase of chitosan, antibacterial action strengthens gradually, and its reason mainly is that molecular weight is big more, and formed outer membrane is fine and close more, can stop nutrient substance to enter bacterial cell more, thereby the antibacterial action effect is more obvious.To gram negative bacteria, more little with the molecular weight of chitosan, antibacterial action strengthens gradually, and molecular weight is that antibacterial action is the strongest below 5000.Its reason mainly is that molecular weight is more little, in the easy more gap structure that enters cell wall, and the metabolism of interference cell, killing bacteria.About chitin and chitosan and the antiviral report of derivant thereof but comparatively rare.
Of the present invention studies show that, chitin and chitosan and derivant thereof have good broad-spectrum disease resistance cytotoxic activity, the activity that can suppress SARS virus, can be made into good anti-virus formulation, can be used for treating many viral diseases such as influenza, atypical pneumonia, chronic type b, hepatitis C, pneumonia, epidemic hemorrhagic fever, viral meningitis, condyloma acuminatum, herpes.
Summary of the invention
The purpose of this invention is to provide the new purposes in chitin and chitosan and derivant thereof the viral infection in prevention or treatment human or animal, chitin or chitosan and derivant antiviral spectrum thereof are wide, effective to SARS virus, prevention and the viral disease that causes of treatment there are good result, and do not have unnecessary toxic and side effects.
Another object of the present invention provides antiviral agent or the disinfectant of being made by chitin and chitosan and derivant thereof, wherein contains chitin or chitosan and the derivant and the medicine acceptable carrier of acceptable treatment effective dose of medicine or sterilization effective dose.
The present invention is by the antiviral experiment in vitro, comprise that pathological changes caused by virus (CPE) suppresses experiment, blood clotting suppresses experiment, inducement interferon experiment, and zoopery and histopathological examination, observe chitin or chitosan and derivant thereof to the cytopathogenic inhibitory action of virus, to the blocking effect of viral infection, to the direct killing effect of virus.The result shows that chitin and chitosan and derivant thereof have the broad-spectrum antiviral activity.
" virus " of the present invention includes but not limited to general DNA and RNA viruses and retrovirus.DNA viruses comprises Parvoviridae, papovaviridae, Adenoviridae, herpetoviridae, Poxviridae and Hepadnaviridae.RNA viruses comprises Picornaviridae, Togaviridae, Rhabdoviridae, orthomyxoviridae family, Paramyxoviridae, coronaviridae, Reoviridae, RNA oncovirus section and filamentous form virus section.Especially comprise DNA viruses herpeslike virus section, Adenoviridae, the Paramyxoviridae of RNA viruses class, orthomyxoviridae family, Picornaviridae, coronaviridae, Togaviridae, Rhabdoviridae.The varicella zoster virus (VZV), the sick I of herpes simplex of Simplexvirus, the II type (HSV-I, II) that comprise the herpetoviridae Varicellavirus more; Adenovirus 3,7 types (AdV3,7) of Adenoviridae Adenovirus; The mouse pneumonia virus of the Measles virus of Paramyxoviridae Morbillivirus (MV), Pneumovirus, respiratory syncytial virus (RSV) and parainfluenza virus-I; Orthomyxoviridae family's Influenza Virus influenza virus (A3V), influenza virus A-prime Mus lung adapted strain FM1 (being used in vivo test); Poliovirus III type (PVIII), echovirus 6,11 types (ECHO6,11), Coxsackie virus B 3,4,5,6 types (CVB3, CVB4, CVB5, CVB6), coxsackie virus A 16 (CVA16), newtype enteroviru 71 types (EV71) that the Picornaviridae enterovirus belongs to; The SARS virus of coronaviridae coronavirus genus; The rubella virus of Togaviridae rubella virus genus (RV); The vesicular stomatitis virus (VSV) that the Rhabdoviridae Vesiculovirus belongs to.
The general molecular weight of chitin of the present invention and chitosan and derivant thereof is below 200,000, with molecular weight below 20,000, water solublity is good preferably.The high chitosan of chitin and deacetylation is easily crystallization all, and is water insoluble, and 40～80% deacetylations, the particularly chitin of 50% left and right sides moderate deacetylation then have extraordinary water solublity, and molecular weight low aqueous solubility is good more more.Compare with high molecular chitosan, molecular weight is lower than 10,000 low molecular chitosan and has better dissolubility, higher antiviral activity.Oligochitosan (Chitosan oligosaccharide), or claim chitin oligosaccharide, formal name used at school is β-1,4-oligomerization-glucamine, for molecular weight less than 10,000 oligomer, nearly 100% in the human body internal absorption factor, antiviral effect is fine.The degree of polymerization is lower than 10 oligomeric chitin or chitosan, and perhaps the antiviral effect of their salt example hydrochloric acid salt or sulfate is all fine, comprising disaccharidase and monosaccharide, as 4-O-(2-Amino-2-deoxy-.beta.-D-glucosyl)-D-glucosamine., 2-amino-D-glucamine (C
6H
11NO
4), chitosan hydrochlorate (C
6H
13NO
5HCl), particularly the degree of polymerization is 3～7 N-acetyl oligo-chitosan or the oligo-chitosan that takes off acetyl, and is even more ideal as the antiviral effect of shell hexose, shell heptose.After OH base on chitin or the chitosan or the suitable replacement of NH2; can be made into water solublity chitin or chitosan derivatives preferably; for example; carboxymethyl or butylation; the salinization of N-quaternary ammonium, sulfonation or N-sulfation, hydroxylating; two (or three) second aminoethylizations etc., typical thing have N-carboxymethyl chitosan, N-carboxylic benzyl chitosan, N-carboxylic butyl chitosan, N-sulfation chitosan, N-quaternary ammonium salt chitosan, Chitofilmer, triithylamine base second class chitin, carboxylic acylation chitosan etc.In addition, by grafting or compoundly also can increase water solublity, but generally with the chitosan molecule amount below 20,000 for well.
Above-mentioned chitin and chitosan and derivant thereof have spectrographic antiviral activity, and the viral infection that DNA and RNA viruses and retrovirus are caused produces effect, but then are not specific for a certain virus, therefore the virus after the variation are also produced effect.
Can use any suitable dispenser type or pattern chitin of the present invention and the chitosan and the derivant medicament thereof of effective dose to be provided for mammal, especially people.For example, can use oral, non-intestinal and local dispenser.Dosage form comprises tablet, capsule, powder, solution, dispersant, suspension, Emulsion, ointment and aerosol and outside sterilization with medicament etc.Pharmaceutical composition of the present invention contains as the chitin of effective ingredient and chitosan and derivant medicament and medicine acceptable carrier and optional other therapeutic component that contains.Chitin of the present invention and chitosan and derivant medicament thereof can be united use with other medicament, and described other therapeutic component includes but not limited to antiviral agent, anticarcinogen, immunostimulant or inhibitor, antiinflammatory, cytokine etc.
Virus is a kind of microorganism of acellular form, and its infection is the infection of molecular level.Because its genome only contains a kind of type nucleic acid (RNA or DNA), lack energy-producing enzyme system in the body, can only colonize in and rely on host cell to supply raw materials in the living cells and enzyme system is carried out virus replication propagation.It passes through: 1. cytocidal effect causes that the cell fusion destroys; 2. integrated infection causes the host cell canceration; 2. cause that immunne response causes the host cell damage finally to cause corresponding disease.Chitin of the present invention and chitosan and derivant antiviral activity thereof may mechanism as follows: chitin and chitosan and derivant thereof have intensive adsorption, make virus be difficult to adhere to and penetrate in the cell, influence virus duplicate propagation; Chitin and chitosan and derivant thereof activate reticuloendothelial system and cell immune system, strengthen huge cytophilic phagocytosis, the reinforced immunological function, make the T lymphocyte discharge the cell that multiple lymphokine participates in killing and wounding infective virus, and stop viral nucleic acid and protein in host cell, to be combined into virion.
The specific embodiment
To be easier to understand the present invention with reference to the following example, and provide embodiment and be in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Embodiment one water-soluble chitosan antiviral effect
(1) materials and methods
1. cell Hep-2, Hela, 3 kinds of cells of BHK21 all go down to posterity with the Eagle culture medium culturing; The PRK cell is taken from the 5d newborn rabbit in age. cultivates with 5% milk protein hydrolysate.
2. viral VZVJ1 strain titre is 10
-5TCID50/ml, the HSV-1 titre is 10
-7TCID50/ml, RVGos-10 strain titre is 10
-6.25TCID50/ml, RVJR23 strain titre is 10
-5TCID50/ml.
3. medicine: water-soluble chitosan, molecular weight 16000～20000, deacetylation are 60%; Acycloguanosine (Acy) is mixed with 1g/L with the Hanks buffer, and 4 ℃ of preservations are standby.
4. after every kind of cell of cell toxicity test grows up to monolayer, change the liquid of keeping that contains 2% calf serum into, add the medicine of variable concentrations, cultivate 96h for 37 ℃, every day the observation of cell metamorphosis.
(2) medicine antiviral experiment
1. water-soluble chitosan is to the inhibitory action of cell qualitative change (CPE) due to the virus: every kind of cell virus inoculation when growing up to monolayer, the medicine that adds variable concentrations simultaneously, each concentration 4 pipe, keeping liquid in 33 ℃ of cultivations with what contain 2% calf serum. CPE reaches when virus control ++ ++ the time, judged result.
2. water-soluble chitosan is to the blocking effect of viral infection: every kind of cell forms the medicine that adds variable concentrations behind the monolayer, cultivates 48h in 37 ℃, discards the liquid of keeping that contains medicine, with Hanks buffer washing 3 times, adds virus attack, cultivates 72h at 33 ℃.
Water-soluble chitosan to virus direct killing effect: with 10000mg/L water-soluble chitosan and viral liquid mixed in equal amounts, handle 12h and 34h respectively in 37 ℃, each times 4 pipe. use the mixed flow inoculating cell, at 33 ℃ of absorption 1h, then with Hanks buffer washing 3 times, remove medicine, at 33 ℃ of cultivations, two CPE production of examining.The virus that does not add medicine is used with the quadrat method processing in contrast.
(3) result
Water-soluble chitosan to each concentration group of toxicity of different cells to every kind of equal free of toxic effects of cell.Cellular morphology is normal.Point out this medicine that the effect that promotes the cell growth is arranged.The cytotoxicity dosage of Acy is 5000mg/L.
2. water-soluble chitosan is to the inhibitory action of CPE due to the VZV: during drug level＞100mg/L, the CPE due to VZV, the HSV is had inhibitory action, medicine is pointed out the acellular difference of antivirus action of this medicine to the effect degree unanimity of virus on every kind of cell.Effective inhibition concentration to RV JR23 and RV Gos-10 is respectively 5000mg/L and 10000mg/L.
3. water-soluble chitosan is invaded the blocking effect of cell to virus: during drug level＞5000mg/L, can alleviate and continue the CPE that VZV causes, with the virus control group evident difference be arranged, point out that this medicine is heavy dose of uses the effect that the infection blocked is just arranged.
4. water-soluble chitosan is to the direct killing effect of virus: the water-soluble chitosan of 10000mg/L is mixed with VZV and HSV suspension respectively, in 37 ℃ of effect 24h virus infectivity is obviously weakened.
This experiment shows that water-soluble chitosan is in the external effect that more tangible anti-VZV, HSV, RV are arranged, and it is obvious to increase antivirus action with dosage, and can produce the effect of direct destruction and blocking-up infection to virion, points out the multiformity of its effect.VZV and HSV belong to DNA viruses, and RV belongs to RNA viruses, and water-soluble chitosan all has effect to them. show that its antiviral spectrum is wide.
Embodiment two oligochitosan antiviral effect
(1) experiment material
1. medicine: oligochitosan, molecular weight 3000～5000.
2. animal: white mice, closed colony Switzerland kind, 13～15g, male and female are regardless of.
3. viral: influenza virus A-prime Mus lung adapted strain FM1 is used in vivo test, for this laboratory is stored in-60 ℃ of cryogenic strains; Parainfluenza virus-I, respiratory syncytial virus (RSV), adenovirus 3,7 type (AdV3,7), intestinal Echovirus 11 (ECHO11), Coxsackie virus B 4,5,6 type (CoxB4,5,5), the sick I of herpes simplex, II type (HSV-I, II), use through going down to posterity after.
4. cell: people's laryngeal carcinoma passage cell Hep-2 strain.
5. cell culture fluid: the Eagles liquid that contains 10% calf serum, 0.29mg/ml glutamine, 100u/ml penicillin and streptomycin; Cell maintenance medium; Except that contained calf serum is 2%, all same culture fluid of other content.
6. traget antibody: goat-anti is exempted from IgG-FITC, and 4 ℃ of preservations are standby.
7. immune serum: with the influenza virus FM1 immunizing rabbit that chick embryo allantoic liquid goes down to posterity, obtain high immune serum of tiring, freeze in one 60 ℃ of refrigerators standby.
(2) experimental technique
1. oligochitosan is to the toxicity test of Hep-2 cultured cell: medicinal liquid is made 1: 4～1: 1024 doubling dilution with cell culture fluid, adding the 96 hole microtest plates of falling in lines has grown up on the Hep-2 cell monolayer, every hole adds 100ul, and each dilution factor respectively adds 4 porocytes, establishes the normal cell contrast simultaneously.Culture plate is put 37 ℃ of 5%CO
2Cultivated in the incubator 4 days, observe the influence of medicinal liquid pair cell with inverted microscope every day, and the minimum dilution factor that regression do not occur with cell is judged to the nontoxic boundary of this medicine pair cell.
2. oligochitosan is to the influence of pathological changes caused by virus effect: get the culture plate that grows up to cell monolayer, outwell culture fluid, inoculate 100 TCID
50Different virus liquid 50ul in cell hole, 37 ℃ of 5%CO are put in every kind of virus inoculation 8 holes
2Absorption is 1 hour in the incubator, outwells viral liquid, with after keeping liquid and washing cell face 3 times, adds 1: 256,1: 512 dilution factor medicinal liquid 100ul.Establish 4 matched groups such as virus, medicinal liquid, positive control drug virazole, normal cell simultaneously.Cultivated 4 days, every day, with the inverted microscope microscopy once observation of cell had or not pathological changes.Continuous 4 days.Cell the degree of pathological change occurs by following 4 grade standard records.+: cytopathy accounts for below 25% of whole cell monolayer; ++: cytopathy accounts for below 50% of whole cell monolayer; +++: cytopathy accounts for below 75% of whole cell monolayer; ++ ++: cytopathy accounts for more than 75% of whole cell monolayer.According to the cytopathy degree, use the rank test method, relatively administration group and virus control group have there was no significant difference.All test hole cytopathy degree and virus control group have significant difference person, have been judged to inhibitory action (+), otherwise are judged to unrestraint effect (-).Test all repeats through 2 times.
3. oligochitosan is to the influence of viral pneumonia due to the influenza virus infecting mouse: mice is divided into 6 groups at random by body weight, and wherein 3 groups give oligochitosan respectively, and 3 groups are respectively the virazole group, virus control group, normal control group.Matched group gives identical medicinal liquid volumetrical distilled water.Except that the normal control group, mice is slightly anaesthetized with ether, with 15LD
50Influenza virus drop nose infects, every 0.05ml.Begin administration or water, every day 2 times the previous day from infecting. each 0.5ml, continuous 5 days, took by weighing body weight on the 6th day, dissection is got lung and is weighed, the perusal pulmonary lesion, record pulmonary liver sample consolidation degree is calculated the lung exponential quantity one by one, and is obtained lung index suppression ratio.Heavy (the g)/body weight (g) * 100 of lung index=lung; Lung index suppression ratio=[virus control group lung index average-test group lung index average] ÷ virus control group lung index average * 100%, the lung exponential quantity is big, and expression lung weight is big, and pneumonopathy range degree is serious.Each group lung index is organized a t check.
4. oligochitosan is to the influence of influenza virus in the internal breeding of Mus lung: removing the viral infection amount is 1000LD
50Outward, animal grouping, medication etc. are all the same.Experimental group gives oligochitosan 6 from infecting the previous day, and 12.24g/kg/d put to death mice in 48 hours behind the infective virus, dissected and got lung, won left side middle period lung and fixed, and pressed the conventional dehydration of pathological section, embedding, making paraffin section.Dye with indirect immunofluorescence, it is former to do spike with fluorescein-labeled resisiting influenza virus serum, by the indirect immunofluorescence combination, observe the virus antigen of infected mice lung internal specific, judge the effect of medicine to virus multiplication, fluorescence positive rate height shows that virion propagation is many, administration group fluorescence positive rate reduces, and shows that medicine has duplicated the inhibition effect to virus. have antivirus action.
(3) experimental result
Oligochitosan has inhibitory action to parainfluenza-1, RSV, ECHO11, CoxB4, B5, B6, HSV-II pathological changes caused by virus, when liquor strength increases to 4mg/ml, AdV3, HSV-1 virus is also had inhibitory action.Oligochitosan becomes pneumonopathy due to the influenza virus infecting mouse inhibitory action.Oligochitosan has significant effect to proliferation of influenza virus amount in the mouse lung, has tangible resisiting influenza virus effect.
The chitosan antiviral effect of embodiment trimerization right 3～7
(1) materials and methods
1. cell line: human amniotic cell (FL), HEKC (293), human cervical carcinoma cell (HeLa).
2. animal: Kunming mouse, male and female half and half, 18～20g, 4 ages in week.
3. viral: Coxsackie B virus 3, B4 (CVB3, CVB4), coxsackie virus A 16 (CVA16), newtype enteroviru 71 types (EV17), poliovirus III type (PVIII), echovirus 6 types (ECHO6V), adenovirus III type (Adv III), herpes simplex virus I-type, II type (HSV-1, HSV-2), respiratory syncytial virus (RV), SARS virus, influenza virus (A3V), Measles virus (MV), rubella virus (RV), vesicular stomatitis virus (VSV).
4. medicine and reagent: the chitosan of the degree of polymerization 3～7.
(2) instrument and method
1. instrument: enzyme mark analyzer, LBK ultraviolet-uisible spectrophotometer, LC-9A infusion pump, refrigerated centrifuge, Olympus phase contrast microscope.
2. the screening of cell and preparation: used 14 kinds of viruses are inoculated in FL, HeLa and 293 cells respectively to measure sensitivity, and cell goes down to posterity according to a conventional method.Make 2 * 10 simultaneously
-5/ ml cell suspension, every hole 0.1ml, it is standby to form cell monolayer behind the 24h.
3. virus virulence is measured: adopt TCID
50Micromethod, the 100-TCID of employing different virus
50/ 0.1ml.
4. primary dcreening operation and grouping experiment: form the cell monolayer hole and discard culture fluid, add the drug effect 24h of pair cell avirulence concentration, the sucking-off medicinal liquid adds viral liquid, by the time of general virus absorption, all adopt 37 ℃ of absorption 1h sucking-off, add the liquid of keeping of pastille, put 37 ℃, 5%CO
2Calorstat is cultivated 48～96h, treats that virus control hole pathological changes reaches ++ +～++ ++, the result is just often surveyed in the cell contrast.Divide 4 groups with the significant virus of primary dcreening operation and experimentize, inquire into the concrete effect link of medicine.The I group: 24h administration before infecting, the sucking-off medicinal liquid uses Hank ' s liquid to wash 3 times, adds viral liquid.II group: infect the back administration, first liquid feeding is put 37 ℃ of absorption 1h flush away viruses and is added pastille and keep liquid.The III group: medicinal liquid and virus add cellular layer simultaneously.IV group: medicinal liquid adds cellular layer with viral the mixing after putting 37 ℃, 2h.Below all establish normal control and virus control.
5. the foundation of infected animal model and dosage regimen: viral myocarditis, pancreatitis, the pneumonia modelling is referring to document.It is 3～7 chitosan variable concentrations administration group that laboratory animal is divided into viral infection model group, normal control group, the degree of polymerization at random, other similar medicine comparable group, and 10 every group, all raise under the same conditions, be the ip administration.
6. the result measures: 1. observation of cell pathological changes (CPE) under the light microscopic; 2. people's method is taken the photograph in dyeing; 2. medicine calculates the histiocyte protective rate.In 1 week of successive administration, aseptic mice pancreatic, lung, the heart got done pathology, histological examination respectively, judges curative effect of medication.
(3) result
Utilize light microscopy checking CPE, the result shows that the degree of polymerization is that 3～7 chitosan can suppress 14 kinds of viruses to some extent to histiocytic CPE.Under mirror, observe on the CPE basis, use the violet staining cell, measure absorbance, so that further reflect the difference of dosing and not dosing objectively.The I group: can experiment purpose be to observe medicine enter cell or be adsorbed in cell surface, to stop viral absorption and to penetrate.The result shows, the degree of polymerization be this method of chitosan of 3～7 to A3V, AdVIII, RSV, HSV-1, HSV-2, EV71, SARS, CVB3, CVB4,10 kinds of meaningful (P＜0.05=of virus of CVA15.The II group: can experiment purpose be to observe medicine work to entering intracellular virus, suppresses its biosynthesis and ripe release.The result shows, the degree of polymerization be this method of chitosan of 3～7 to A3V, AdVIII, MV, RSV, HSV-1.HSV-2, SARS, CVB3, CVB4, CVA15,11 kinds of meaningful (P＜0.05=of virus of EV71.III, IV group: for medicine and virus act under different condition, observe medicine to the direct deactivation of virus, the result shows. the degree of polymerization is that 3～7 chitosan all has effect to 13 kinds of viruses except that RV.Illustrate the degree of polymerization be 3～7 chitosan no matter be medicine and virus add simultaneously cellular layer or medicine and virus earlier effect 2h add cellular layer then, all have antiviral effect.The protective rate of pair cell reaches as high as 96%.The degree of polymerization is that 3～7 chitosan has significant protective effect to pancreatitis and myocarditis due to the CVB4 viral infection; treatment group pancreatic tissue structure is normal substantially. a small amount of lymphocyte infiltration is arranged. and the necrosis of myocardium rarely seen special mess shape; virus control Mus pancreas has big amount lymphocyte and segmented cell to invade profit, the necrosis of myocardium large stretch of kitchen range shape.SHUANGHUANLIAN has protective effect to Mice.
Embodiment four water solublity chitin oligosaccharide antiviral effect
(1) experiment material
1. virus is used cell with experiment: Coxsackie virus 3,5 types (CB3, CB5), SARS virus, adenovirus 3,7 types (AdV3, AdV7), syncytial virus (RSV), influenza virus, parainfluenza virus, blister stomatitis virus (VSV).The Hep-2 cell derives from people's larynx epithelial cell cancerous cell line.
2. medicine: water solublity chitin oligosaccharide, molecular weight 1500～1600.
(2) method
1. to the external anti-viral experiment of CB, AdB, RSV, SARS virus: 1. test to select for use experiment is made 1 * 10 with the virus sensitivity with cell
5-6The Hep-2 cell of the cell suspension of ten thousand/ml.2. laboratory sample is used cytotoxic assay to experiment: sample is done 2 times of serial dilutions with cell maintenance medium since 1: 10 concentration, and the drug level with to 50% cell toxigenicity the time is CC
503. viral infection titer determination: the fresh viral suspension of getting CB3, CB5, AdV3, AdV7, RSV, SARS, be diluted to different dilution factors with 10 times of successive dilution methods, be inoculated into respectively in tissue culture's cell monolayer pipe, every pipe inoculation 100ul, 4 cell pipes of each dilution factor inoculation, virus is fully contacted with cell, 37 ℃ of absorption 1h, wash 3 times with Hank ' s liquid, add cell maintenance medium, 37 ℃ of cultivations, observed and recorded cytopathy situation under simple microscope day by day, observe 1～5d, measure the median infective dose TCID of tissue culture
50The 100TCID of different virus is selected in this experiment for use
50/ 0.5ml.4. the neutralization experiment is made serial doubling dilution, 1 medicine and 100TCID with sample from the not toxigenous last hole of pair cell concentration
50Viral equivalent addition, shake up and put 37 ℃ of water-bath effect 1.5h, be inoculated in 96 well culture plates that form cell monolayer, establish virus control, normal cell contrast, Chinese medicine matched group simultaneously, to produce the high dilution of 50% cytopathic medicine as result of determination.
2. the blood clotting to influenza, parainfluenza virus suppresses experiment: get 96 well culture plates, the sample order is made doubling dilution to 1: 5120, every hole adds the hemagglutinin 100ul mixed in equal amounts of 4 units, 37 ℃ of effect 1h, add each 100ul of 1% chicken red blood cell, shake up rearmounted room temperature 30 ', 45 ' and respectively observe the result 1 time, be as the criterion with 45 '.Matched group is established medicine contrast, virus control (add each each 100ul of 100ul+ normal saline of 4,2,1,1/2 unit hemagglutinin, erythrocyte contrast respectively, more than each matched group add 1% chicken red blood cell 100ul more respectively, shake up, under the same conditions observed result.With the minimum drug level that can suppress red cell agglutination fully is terminal point.
4. sample induces human leukocyte interferon titration experiment: 1. sample inducement interferon: with the centrifugal 1min of 100ml Freshman whole blood 3000rpm, separated plasma is got hemocyte and is added 3 times of amount 0.83%NH
4Behind the Cl effect certain hour, low-speed centrifugal is left and taken leukocyte, is diluted to 2,000,000 units/ml, and with different dilution medicament mixed, 37 ℃ of shaking tables rock cultivates 18h, and centrifugal, supernatant is a interferon that induces.2. interferon titration: the interferon that each dilution factor of every group of sample induces is done 4 times of dilutions respectively, be inoculated in the well culture plate that forms cell monolayer, establish 5 groups of contradistinction systems simultaneously: medicine contradistinction system, VSB virus control system, medicine+VSV virus control system, interferon (IFN) contradistinction system, normal cell contradistinction system.Hatch 24h for 37 ℃, every hole adds 100ul 100TCI
50VSV virus (medicine contrast and normal cell contradistinction system add keep liquid), the cell for the treatment of control wells all or 75% abovely read the result when obvious pathological changes takes place are judged the dilution factor of the sample inducement interferon of protecting 50% cellular immunization virus damage.
(3) result
The water solublity chitin oligosaccharide all has the inhibition effect to CB3, CB5, AdV3, AdV7, RSV, SARS.From the titration result of sample inducement interferon, along with diluted sample, the ability of inducement interferon descends gradually, proves the antiviral and the immunoregulation effect of water solublity chitin oligosaccharide.
Claims (6)
1. chitin and chitosan are in varicella zoster virus, the sick I of herpes simplex of Simplexvirus, the II type of preparation anti-herpesvirus section Varicellavirus; Adenovirus 3,7 types of Adenoviridae Adenovirus; The Measles virus of Paramyxoviridae Morbillivirus, the mouse pneumonia virus of Pneumovirus, respiratory syncytial virus and parainfluenza virus-I; Orthomyxoviridae family's Influenza Virus influenza virus, influenza virus A-prime Mus lung adapted strain FM1; Poliovirus III type, echovirus 6,11 types, Coxsackie virus B 3,4,5,6 types, CA l6, newtype enteroviru 71 types that the Picornaviridae enterovirus belongs to; The SARS virus of coronaviridae coronavirus genus; The rubella virus of Togaviridae rubella virus genus; Application in the medicament of the vesicular stomatitis virus that the Rhabdoviridae Vesiculovirus belongs to.
2. the described application of claim 1 is characterized in that, described virus is the SARS virus of coronaviridae coronavirus genus.
3. claim 1 or 2 described application is characterized in that, described chitin and chitosan molecule amount be below 20,000,40～80% deacetylations.
4. claim 1 or 2 described application is characterized in that, described chitin and chitosan are that molecular weight is lower than 10,000 oligochitosan.
5. the described application of claim 4 is characterized in that, described chitin and chitosan are that the degree of polymerization is lower than 1～10 oligomeric chitin or chitosan, or their hydrochlorate or sulfate.
6. the described application of claim 5 is characterized in that, described chitin and chitosan are that the degree of polymerization is 3～7 N-acetyl oligo-chitosan or the oligo-chitosan that takes off acetyl.
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Cited By (2)
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| WO2011114346A1 (en) * | 2010-03-18 | 2011-09-22 | Chetan Balar | Chitin and related compounds for use in treating bacterial and viral infections |
| WO2022043678A1 (en) * | 2020-08-24 | 2022-03-03 | Nanomerics Limited | Viral inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011114346A1 (en) * | 2010-03-18 | 2011-09-22 | Chetan Balar | Chitin and related compounds for use in treating bacterial and viral infections |
| WO2022043678A1 (en) * | 2020-08-24 | 2022-03-03 | Nanomerics Limited | Viral inhibitors |
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