CN108042519A - Application of the caffeic acid in anti-HPV viruse infection medicine is prepared - Google Patents
Application of the caffeic acid in anti-HPV viruse infection medicine is prepared Download PDFInfo
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Abstract
The invention discloses application of the caffeic acid in anti-HPV viruse infection medicine is prepared, and belong to biomedical sector.Inventor has found that caffeic acid has preferable anti-HPV viruse infection activity for the first time by research, can be effectively blocked HPV viruse and stick target cell, so as to inhibit the infection of HPV viruse.The experiment proves that caffeic acid can directly with virus capsid protein be combined, antagonism virus to target cell stick have the function that it is antiviral.Caffeic acid acts on viral early stage into the stage of cell, and can act on the mid-term and late stage of cell entry simultaneously.Its effect is better than acting only on the drug of cell entry cell early stage in the prior art.Meanwhile caffeic acid is harmless in the concentration range for playing antivirus action, has high use value and security.Caffeic acid is very likely developed into the novel microbiocides of the virus infection that spread through sex intercourse such as a new generation prevention and treatment HPV.
Description
Technical field
The invention belongs to biomedical sectors, and in particular to caffeinic new opplication.
Background technology
Human papilloma virus (human papillomavirus, HPV) is a kind of thermophilic epithelium virus, belongs to papovavirus
Section's Papillomavirus is molecule amount smaller (7.9Kb) without the thermophilic epithelial DNA virus of coating double-stranded circular.Have at present
The HPV of about 200 kinds of different subtypes is divided into low risk and high-risk-type according to the difference of its degree of causing a disease.The HPV of low risk is main
Cause low lesion, genitals or the cutaneous wart and condyloma acuminatum of infection site, and high-risk HPV then mainly causes infection site
Height lesion and invasive cancer.The persistent infection of high-risk HPV simultaneously has proved to be the important of the generation of induction cervical carcinoma
Risk factor, epidemiological study show 90% cervical carcinoma all with the infection of high-risk HPV.And the cervical carcinoma more than 80%
Developing country is happened at, there are about 135,000 women every year to develop into cervical carcinoma, and has more than 266, and 000 people dies of palace
Neck cancer, the second largest main cause of this female cancer death rate between having become 15 to 44 years old.
For the genital wart or the case of cervical carcinoma clinically occurred, no matter whether it infects HPV, at present clinically
Treatment means are mainly physiotherapy, such as cold therapy, lucotherapy, chemical ablation.But physical therapy is inherently
Passive symptomatic treatment, it is intended to remove the infection of the confrontation HPV of lesion rather than specificity.And there is all for physiotherapy
More risk factors, such as massive haemorrhage, stenosis of cervix and cervical incompetence etc., simultaneously because without effectively controlling
There is disease palindromia again after the treatment in the infection of HPV, the patient there are about 10%.
It secures permission at present there are many HPV vaccines in many countries, such as Gardasil and Cervarix, vaccine inoculation
Afterwards, can stimulating immune system generate protection antibody, this antibody is present among the body fluid of people, and HPV viruse resists once occurring
Cognition acts on immediately, is removed, and HPV viruse is prevented to infect, and so as to achieve the purpose that prevent HPV infection, is demonstrate,proved at present
Bright preventative vaccine can prevent the infection of a variety of HPV hypotypes.But the use of vaccine is such as sent out there are still some defects at some
National in exhibition, application nevertheless suffers from the limitation of high cost, shipment and delivery cost and a large amount of virus subtypes.And HPV vaccines are merely able to
Prevent the infection of HPV, that is to say, that HPV vaccines only provide prevention effect rather than therapeutic effect, for having infected the people of HPV
Group's vaccine inoculation is invalid.
Although physiotherapy is still the optimal treatment selection of genital wart, cytotoxic drug such as podophyllotoxin
Also be applied to relevant treatment in US and European with trichloroacetic acid, and 5-fluor-uracil due to its strong inflammatory reaction because
And it is restricted in the treatment of outer genital lesion.Although although the use of these drugs is effective, they do not show
Go out the dose-dependent effect of anti-HPV viruse.In addition, interferon is the currently the only relevant diseases to go through applied to benign HPV
Drug, but it is used treatment successful case be that subcutaneous interferon is carried out after by surgical resection lesions visible
So as to reduce recurrence rate.Only very limited amount of data display interference element is shown in the treatment of HPV relevant diseases and cancer
Effective therapeutic effect.RNA disturb (RNAi) although nucleotide analog can disturb the expression of HPV viruse related gene so as to
Have the function that antiviral, but it only works on post-transcriptional level, and does not have any influence on Virus latency, because
This, RNAi nucleotide analogs can not be applied individually to any the treatment of HPV relevant diseases.In addition, antioxidant and herbal medicine derive
Object also shows that effective treatment potentiality to HPV infection, and wherein the most notable with the achievement in research of herbal derivative, such as
Jamaicin (Berberine), curcumin (Curcumin), promise reach hydrogen guaiaretic acid (NGDA), EGCG etc., these herbal derivatives
Disease caused by can inhibiting HPV infection by the transcription of blocking virus gene or the effect partial of antagonism virus protein,
But although these drugs show efficient antivirus action in development phase, for pregnant women be disabling, in addition,
In clinical research, the problems such as said medicine is due to security and validity and lie on the table, cause the failure of research and development.
Meanwhile the drug candidate of a collection of microbicide, such as Praneem, carrageenan (Carrageenan), turmeric
Plain poly galenical Basant and JB01-BD etc., they can reach pre- by the way that HPV viruse is blocked to invade human body cell
The effect of anti-HPV infection, but likewise, their effect is limited only to the prevention of HPV infection, and can not infect
It is treated in the case of HPV.It is assumed that may be because above-mentioned drug candidate is mainly acted as before Virus entry cell
With, and it is ineffective after Virus entry cell and amount reproduction.
Based on traditional operation treatment means and the defects of HPV vaccines and the shortage of currently valid anti-HPV viruse drug,
It is very necessary to develop the new antiviral drugs for being used to treat or prevent HPV infection.
The content of the invention
It is an object of the invention to provide application of the caffeic acid in anti-HPV viruse infection medicine is prepared.
The technical solution used in the present invention is：
Caffeic acid or its pharmaceutically acceptable salt, fat, glycosylated derivative are preparing anti-HPV viruse infection medicine
Using.
Caffeic acid is one of primary water-soluble ingredient of Salvia root P.E, molecular formula C9H8O4, molecular weight 180.15, be from
Fortified aqueous obtains yellow crystal, and monohydrate is obtained from dilute aqueous solution.223~225 ° of decomposition point (softens) at 194 °.It is slightly soluble in cold
Water is soluble in hot water and cold ethyl alcohol.Structural formula is as follows：
Research finds that caffeic acid has anti-oxidant, cardioprotection, protection brain, antitumor action, at present in cardiovascular and cerebrovascular disease
The effect of notable is shown in the treatment of disease and tumour.
Applicants have found that caffeic acid (Salvianolic Acid B), has preferable anti-HPV viruse infection activity,
HPV viruse can be effectively blocked and stick target cell, so as to inhibit the infection of HPV viruse.
A kind of drug of anti-HPV infection, the active ingredient of the drug of the anti-HPV infection include caffeic acid or its pharmaceutically
At least one of acceptable salt, fat, glycosylated derivative.
Preferably, the dosage form of the drug of the anti-HPV infection includes at least one of gel, butterfat, suppository.
A kind of microbicide of anti-HPV infection, the active ingredient of the microbicide of the anti-HPV infection include coffee
Acid or its pharmaceutically at least one of acceptable salt, fat, glycosylated derivative.
Preferably, the dosage form of the microbicide of the anti-HPV infection includes at least one of gel, butterfat, suppository.
Caffeic acid is except with anti-HPV viruse infection activity, applicant has found that caffeic acid can be effective in early-stage study
Inhibit the formation of ripe SEVI amyloid fibers, so as to inhibit the inhibition of HIV of SEVI infection humidification, and form sediment to SEM1
The formation of powder sample fiber also has inhibitory action.Therefore, caffeic acid can be as a kind of double work(with efficient anti-HPV, HIV activity
It can candidate microbicide.
The beneficial effects of the invention are as follows：
The invention discloses a kind of drug -- caffeic acids that HPV viruse is blocked to infect.Applicant has found coffee by research
Coffee acid itself has efficient anti-HPV activity, can act on the early stage of cell entry cell.Caffeic acid passes through straight simultaneously
Targeting virus is connect, the Major capsid protein L1 with playing main function in cell entry cell stage has high affinity, can
Combined with direct with viral capsid protein, so as to antagonism virus to target cell stick have the function that it is antiviral.
Inventor establishes external pseudovirus infection activity drug screening cell model, and experimental result is shown, caffeic acid can be with
Virus infection caused by directly blocking the human papilloma pseudovirus of tri- kinds of hypotypes (HPV6, HPV16, HPV18) of HPV, and with dense
Spend dependence.Time-of-addition experiments confirm that caffeic acid is blocked by acting on the preliminary stage of cell entry target cell
Direct viral infection target cell, and the mid-term and late stage of cell entry cell can be acted on simultaneously, and in cell entry
The early stage inhibiting rate of cell is maximum, and effect is best.Its effect is early better than cell entry cell is acted only in the prior art
The drug of phase.Time-of-removal experiments confirm that caffeic acid is directly targeted and act on the work that virus plays blocking virus infection
With.For Temperatureshift it is experimentally confirmed that caffeic acid acts on the early stage of virus infected cell, directly prevention virus is glutinous
Attached target cell.The ability of the viral Major capsid protein L1 of detection caffeic acid combination is tested by surface plasma resonance (SPR), it is real
Verification understands that the major capsid protein that caffeic acid can be directly with virus is combined, so as to which antagonism virus reaches sticking for target cell
Antiviral effect.Meanwhile it is played in caffeic acid substantially acellular to human normal cell in the concentration range of antivirus action
Toxicity, to sum up, caffeic acid have high use value and security in terms of HPV viruse infection is prevented.Caffeic acid pole has can
It can be developed into the novel microbiocides of the virus infection that spread through sex intercourse such as a new generation prevention and treatment HPV.
Caffeic acid derives from a wealth of sources, and originating species Radix Salviae Miltiorrhizae has very long answer as edible and medicinal plant in China
With history, relative price is cheap, securely and reliably.
Description of the drawings
Fig. 1：External pseudovirus infection model detection caffeic acid is to the inhibitory action of HPV pseudovirus.
Fig. 2：Time-of-addition experiment detection caffeic acids act on the early stage of virus infected cell.
Fig. 3：Time-of-removal experiment detection caffeic acid targetings are in virus.
Fig. 4：Temperature shift experiment detection caffeic acid blocking virus stick target cell.
Fig. 5：Surface plasma resonance experiment detection caffeic acid combines the ability of viral Major capsid protein L1.
Fig. 6：Cytotoxicity experiment result.
Specific embodiment
Below in conjunction with experiment, the present invention is further described, but protection scope of the present invention is without being limited thereto.
Experiment one：Pseudovirus infection model detects inhibitory action of the caffeic acid to HPV pseudovirus
Experimental method：
1) gradient dilution caffeic acid adds in after incubating 30min altogether with the isometric mixing of HPV6/HPV16/HPV18 cape horn fever venom
In the Tissue Culture Plate being inoculated in advance, virus control wells and cell blank control wells are set；
2) change fresh culture afterwards for 24 hours, Luciferase Assay Reagent box detection cell fluorescence element is used after virus infection 48h
Expression of enzymes situation.
Experimental result is as shown in Figure 1, caffeic acid can effectively inhibit three kinds of hypotype HPV pseudovirus infection cells, and have dense
Dependence is spent, to the virus IC of HPV6,16,1850It is 12.06 ± 0.40,12.92 ± 0.54,16.45 ± 0.80 μ g/ml respectively.
Experiment two：Time-of-addition experiment detection caffeic acids act on the early stage of virus infected cell
Experimental method：
1) HPV6/HPV16/HPV18 type cape horn fevers venom is added in the cell plates being inoculated in advance, is placed in incubator and trains
2h is supported, sucks supernatant, PBS board-washings 2 times add in the fresh DMEM medium containing 10%FBS；
2) by caffeic acid in different time points (0,2,4,6,8,10,12, for 24 hours) add in cell plates in, wherein 0h drugs and
Add in plate after virus incubation 30min, when 2h wash away virus liquid after add in drug immediately；
3) expression of Luciferase Assay Reagent box examining report gene luciferase is utilized after 48h, calculates drug suppression
Rate processed.
Since cell entry cell needs the time (the enough cell entries of 2h are intracellular), shell of undressing is undergone afterwards into cell
Etc. a series of variation, by detecting the difference of each time point after virus infected cell, judge drug caffeic acid be
Which of virus infected cell works in stage, if caffeic acid can play inhibitory action explanation in cell entry SMS message
It plays a role in the early stage drug of cell entry, if caffeic acid does not have inhibitory action rear in the early stage of cell entry
There is inhibitory action to illustrate stage of the drug effect after cell entry cell in time phase, if drug the early and late time all
There is inhibitory action, illustrate that virus acts not only on the cell entry stage, also act on the stage after cell entry cell.
Experimental result is as shown in Fig. 2, the caffeic acid early stage blocking virus that may act on cell entry target cell are direct
Target cell infection.80% is reached to the inhibiting rate of HPV6 in 0h point caffeic acids, HPV16, HPV18 inhibiting rate are nearly reached
100%, for three kinds of strains, extension inhibiting rate is all on a declining curve at any time, and the time that caffeic acid adds in is more early, to virus
Inhibition is better.More than 40% is reached to HPV6 inhibiting rates in 12h point caffeic acids, HPV16, HPV18 inhibiting rate are reached
More than 50%, show that caffeic acid can act on viral early stage into the stage of cell, and cell entry can be acted on simultaneously
Mid-term and late stage, but the early stage inhibiting rate in cell entry cell is maximum, and effect is best.
Experiment three：Time-of-removal experiment detection caffeic acid targetings are in virus
1) caffeic acid that concentration is 100ug/ml is added to per 100 μ l of hole in cell plates, after cultivating 2h, sucks culture
Base is cleaned 2 times with the DMEM blank cultures without serum, adds in the fresh culture containing virus liquid.
Conventional viral Inhibition test is carried out at the same time, by the drug (caffeic acid of final concentration of 100ug/ml) and disease after dilution
Venom (HPV6,16,18) mixes, and is added in after being placed in 37 DEG C of incubation 30min in cell plates, is placed in cell incubator and continues to train
It supports.
2) expression of Luciferase Assay Reagent box examining report gene luciferase is utilized after 48h.
If before virus infected cell, drug is added in it is intracellular, if drug can by targeting cell, such as with
The receptor combined is needed to combine when being infected on cell with virus, occupies virus and the binding site of cell, then remove drug
It is afterwards plus viral, the viral infection cell that can not succeed, whereas if caffeic acid is not combined with receptor, it is thin in cleaning
It can be removed during born of the same parents, pseudovirus is by normal infection cell.It is by directly acting on virus to illustrate caffeic acid, such as is directly killed
Virus of going out prevents virus attachment from working on cell, and specific mechanism of action subsequent experimental proves.
Experimental result is as shown in figure 3, caffeic acid is to play blocking disease by being directly targeted virus rather than acting on cell
The effect of poison infection.
When progress conventional viral Inhibition test compares, the caffeic acid of final concentration of 100ug/ml can almost completely inhibit
The type pseudovirus infection cell of HPV6,16,18.And after the caffeic acid of same concentrations incubates cell in advance and is cleaned, it can not inhibit
Pseudovirus infects, and three kinds of strains obtain identical result.
To sum up, the bright caffeic acid of this verification is by being directly targeted virus rather than being risen by acting on host cell receptor
The effect infected to blocking virus.
Experiment four：Temperature shift experiment detection caffeic acid blocking virus stick target cell
Pass through literature survey early period, it has been found that HPV viruse is to enter cell by pinocytosis endocytosis.Pinocytosis is
One energy consumption process is, it is necessary to consume substantial amounts of energy, and when cell is in 4 DEG C of environment, the efficiency of viral adherent cell compares physiology
It is significantly reduced during temperature (37 DEG C), and on the other hand, low temperature environment has no effect on viral mutual with host cell surface receptor
Effect.More than finding is based on, we devise HPV pseudovirions " Temperature shift " experiment.In 4 DEG C of items
Target cell is incubated with HPV pseudovirus under part, HPV viruse particle is only capable of being incorporated into cell surface, viral endocytosis under the conditions of this
It can not occur, then wash off the pseudovirion that cell surface does not stick, cell is transferred to 37 DEG C of cultures continues to cultivate, physiology
Pinocytosis restarts under the conditions of 37 DEG C of temperature, and the virion for having attached to cell surface enters cell, detected after 48h
Into intracellular virus load.Caffeic acid is added in when this low temperature is incubated, is arranged to the virus control group of dosing.
Specifically, experimental method is as follows：
1) drug of different gradient dilutions and virus liquid are mixed, is placed in 4 DEG C of incubation 30min；
2) the drug disease venene after precooling is added in per 100 μ l of hole in the cell plates of precooling, individually adds virus liquid
Cell hole as virus control wells, cell plates are placed in 4 DEG C of placement 3h by cell hole as blank control；
3) cells and supernatant is sucked after 3h, is cleaned 2 times using the DMEM blank cultures without serum, washes away cell table
The virus that face is not sticked is placed in 37 DEG C of culture 48h；
4) expression of Luciferase Assay Reagent box examining report gene luciferase is utilized after 48h.
Experimental result is as shown in figure 4, for three kinds of strains, the titre of coffee acid treatment group virus is substantially less than virus control
Group, and with concentration dependent, it was demonstrated that caffeic acid acts on the stage of HPV pseudovirion adherent cells, and blocks this mistake
The generation of journey.To sum up, caffeic acid can act on the early stage of virus infected cell, directly virus be prevented to stick target cell.
Experiment five：The ability of surface plasma resonance experiment detection caffeic acid combination viral capsid proteins L1
Experimental method：
1) by Medicine small molecule point sample on 3D Dextran chips, cover is sticked, first carries out being incubated overnight processing, so
Seal treatment is carried out on SPRi instruments afterwards.
2) using 1 × PBS by albumen (viral capsid proteins L1) gradient dilution into 50nM, 100nM, 200nM, 400nM,
800nM, each each 650 μ L of gradient, flow velocity are 2 μ Ls-1, association reaction temperature is 23 DEG C, binding time 300s, during dissociation
Between be 300s.1 × PBS (pH=7.4) is used as mobile phase composition in entire experiment.
3) after each reaction, 0.5%SDS is used:Glycine-HCl (pH=2.0)=1:1 solution is as liquid of living again
(being prepared with ultra-pure water) lives again, and flow velocity is 2 μ Ls-1。
4) 3.0 software analysis results of BIAeval are used；
As shown in figure 5, caffeic acid has high affinity with viral Major capsid protein L1, affinity is experimental result
7.71e-11。
Experiment six：Experiment detects caffeinic cytotoxicity
Experimental method：
1) in the Tissue Culture Plate for being inoculated with the caffeic acid addition of gradient dilution in advance, cell blank control wells are set；
2) discard cells and supernatant after 48h, add in final concentration 0.5mg/ml MTT liquid 100ul/ holes, be placed in 37 DEG C, 5%
CO24h is cultivated in incubator；
3) cell MTT liquid is discarded, adds in DMSO 100ul/ holes, shakes 10min, in wavelength 570nm, measures absorbance.
Experimental result as shown in fig. 6, caffeic acid to the CC of Hela cells50(causing concentration needed for half cytotoxicity) is
139.9 ± 6.6ug/ml, due to the virus IC of caffeic acid HPV6,16,185012.06 ± 0.40 respectively, 12.92 ± 0.54,
16.45 ± 0.80 μ g/ml, CC50It is far longer than IC50, so caffeic acid in the concentration range for playing antiviral left and right to people palace
The basic no cytotoxicity of neck cancer cell.
Claims (5)
1. caffeic acid or its pharmaceutically acceptable salt, fat, glycosylated derivative in anti-HPV viruse infection medicine is prepared
Using.
2. a kind of drug of anti-HPV infection, it is characterised in that：The active ingredient of the drug of the anti-HPV infection includes caffeic acid
Or its pharmaceutically at least one of acceptable salt, fat, glycosylated derivative.
3. drug according to claim 2, it is characterised in that：The dosage form of the drug of the anti-HPV infection includes gel, breast
At least one of fat, suppository.
4. a kind of microbicide of anti-HPV infection, it is characterised in that：The microbicide of the anti-HPV infection activity into
Subpackage is containing caffeic acid or its pharmaceutically at least one of acceptable salt, fat, glycosylated derivative.
5. anti-HPV infection microbicide according to claim 4, it is characterised in that：The anti-HPV infection kills micro- life
The dosage form of agent includes at least one of gel, butterfat, suppository.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108042524A (en) * | 2017-12-21 | 2018-05-18 | 南方医科大学 | The application of tanshin polyphenolic acid B and its analogue in anti-HPV viruse infection medicine is prepared |
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| CN108042524A (en) * | 2017-12-21 | 2018-05-18 | 南方医科大学 | The application of tanshin polyphenolic acid B and its analogue in anti-HPV viruse infection medicine is prepared |
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