CN102343083A - Antivirus composition medicament - Google Patents
Antivirus composition medicament Download PDFInfo
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- CN102343083A CN102343083A CN2011103149724A CN201110314972A CN102343083A CN 102343083 A CN102343083 A CN 102343083A CN 2011103149724 A CN2011103149724 A CN 2011103149724A CN 201110314972 A CN201110314972 A CN 201110314972A CN 102343083 A CN102343083 A CN 102343083A
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Abstract
The invention belongs to the technical field of biological medicine and particularly relates to an Interferon (IFNs) synergistic medicament and an antivirus composition medicament of IFNs. The antivirus composition medicament contains IFNs and a flavone compound. The antivirus composition medicament has the advantages of reducing the using amount of IFNs, reducing the side effect, improving the curative effect, and the like.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to the antiviral composition of medicine of a kind of interferon (IFNs) potentiation medicament and interferon (IFNs).
Background technology
Interferon is the antiviral that has by emiocytosis; Antitumor; Extensive bioactive cytokine such as immunomodulating; Mainly contain three types; I type interferon (IFN α s; IFN β etc.); II type interferon (IFN γ) and type iii interferon (IFN-λ s); All this all is effective viral inhibitors for three kinds; Especially I type interferon is important antiviral cell factor; Its antiviral mechanism mainly be the cell behind the infective virus can excretory interferon with the cell that does not infect on every side on the associated receptor effect; Impel the synthetic antiviral protein of these cells to prevent further infection, thereby play antiviral effect.In addition, interferon (IFNs) also has second kind of effect-immunoregulation effect of antagonism viral infection, and obviously the enhance immunity cell activity promotes the scavenging action of immunocyte to virus.
Different with general antiviral drugs is that interferon is a host specific, and the synthetic interferon of the cell of same genus is merely able to discern the receptor on the cell of same genus.So the synthetic interferon of a kind of zooblast can only suppress this kind animal and avoid other viral infection, and can not be applied to other animal opposing viral infection.Human interferon is mainly generated and secretion by leukocyte (IFN α), fibroblast (IFN β), T cell and NK cell (IFN γ), and early stage obtaining of interferon is through inductive mode, gathers the leukocyte in the blood of human body, and extracts through purification technique.Because it is very limited to extract interferon raw material source in this way, contains a lot of impurity, has tangible antigenicity in addition, not only act on limitedly, but also can bring a lot of side effect, thereby limit its clinical practice because of the purity deficiency.
Along with the mankind to the understanding of interferon anti-reflecting virus effect and the development of gene recombinaton purification technique, interferon is applied to the treatment of viral hepatitis gradually, 1991, the drugs approved by FDA interferon-ALPHA was used to treat hepatitis C; 1992, interferon-ALPHA was used to treat hepatitis B by the FDA approval; 2002, the Polyethylene Glycol Intederon Alpha-2a was used for the treatment of hepatitis C by the FDA approval; 2005, FDA official approval Polyethylene Glycol Intederon Alpha-2a was used for the treatment of hepatitis B.At present, interferon especially long-acting interferon become the core medicine of viral hepatitis HBV/HCV.Except that having antiviral, immunoregulatory effect; Also has obvious antineoplastic; Therefore; Interferon has been used to treat multiple cancer and leukemia at present; Like Polyethylene Glycol Interferon Alpha-2b interferon; Obtain the FDA approval in 2011, be used for the auxiliary treatment of malignant melanoma treatment and lymphatic metastasis.
The JAK-STAT signal pathway; It is the signal pathway that is found the interferon activation that also is the research fullest the earliest; In the JAK-STAT approach that interferon (IFNs) activates; Interferon (IFNs) at first with cell membrane on its corresponding acceptor (IFNAR1, IFNAR2) in conjunction with and activate JAK1 and the TYK2 that links to each other with its acceptor; Next the JAKs that activates regulates the stat protein phosphorylation and causes the STAT homology or the allos dimerization; Then STAT dimer or itself and the compound that IRF9 forms transfer in the nucleus with interferon-stimulated gene (ISG) thus the distinguished sequence ISRE of promoter or GAS combine the transcript and expression of activation interferon regulatory gene; Like double-stranded RNA-dependent protein kinase (dsRNA-dependentproteinkinase; PKR) and 2 '; 5 '-oligo-adenylate synthetase (2 '; 5 ' oligoadenylatesynthetase; 2 '; 5 '-OAS); Wherein 2 '; 5 '-the oligo-adenylate synthetase virus mRNA of can degrading, protein kinase PKR can the blocking virus protein translation.
But because interferon must reach higher concentration and just can induce host cell to synthesize antiviral protein in local cells; Therefore can effect of interferon depend on and the interferon of doses is carried or be expelled to focus, and interferon has its inherent shortcoming as pharmaceutical grade protein: unsuitable oral, drug effect/pharmacokinetics weak effect.And the interferon of high dose has serious seondary effect, like leukopenia, bring out autoimmune disease etc.Therefore, searching has the micromolecular compound that interferon (IFNs) is had potentiation, becomes the side effect that reduces interferon, improves the important channel of curative effect.
Though report lentinan (macromolecule glucosan) is arranged; Mannatide; Ubenimex (dipeptides); Polyinosini; Gather gland urine; Pidotimod have potentiation to interference; But mostly be macromolecule polyalcohol; Still there be a difficult problem and the obstacle that needs to be resolved hurrily in use: as be difficult to permeates cell membranes; Strong immunogenicity; Be difficult to penetrate effectively solid tumor; Safety is low; Morphology is complicated (to exist polymorphic; Many conformations and multiple dimensioned) problem such as, and the crystals with different structure is for drug bioavailability; The enforcement function of active (therapeutic effect) and drug delivery all has epochmaking influence.And that flavone compound is distributed widely in is medicinal, in the food plant; Like crude drugs such as Flos Lonicerae, Flos Chrysanthemi, Herba Schizonepetae, Herba Ajugae, arithoke, Perilla, Scutellarias; And in the vegetable fruit such as selenium supplement, cabbage, cauliflower, Radix Betae, Broccoli, Radix Dauci Sativae, Herba Apii graveolentis, Fructus Capsici, Fructus Capsici, Semen arachidis hypogaeae, have certain antiviral activity and safety non-toxic.Though bibliographical information is arranged; Luteolin (Luteolin) separately or associating IFN β be used to treat multiple sclerosis (Multiple Sclerosis); But multiple sclerosis is a kind of central nervous system disease of chronic, struvite, demyelination; Be not that virus causes; And flavone compound according to the invention has the antivirus action of remarkable potentiation interferon (IFNs); The composition of medicine of itself and interferon (IFNs) does not appear in the newspapers as yet.
Summary of the invention
The present invention is directed to above problem a kind of antiviral composition of medicine is provided, this composition of medicine has synergistic function preferably when the treatment relevant disease, can increase efficacy of interferon therapy, improves therapeutic effect.
A kind of antiviral composition of medicine of the present invention is the antiviral composition of medicine of interferon (IFNs) and flavonoid compound, and wherein flavone compound has following general structure:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7Be respectively H or OR ' (R '=H, alkyl, sugar).
Technical scheme of the present invention is: per 1,000,000 IU interferon and above-mentioned flavone compound 2-200mg, add appropriate pharmaceutic adjuvant and make composition of medicine.Prepared Pharmaceutical composition can be used for the treatment of relevant disease, has minimizing interferon (IFNs) consumption, reduces its side effect, improves advantages such as curative effect.
The several problems that need explanation:
1. the interferon (IFNs) in the preparation of the present invention comprises the interferon (IFNs) of the various molecular weight of producing through biological extraction or genetic engineering, also comprises all hypotypes of acceptable and trim thereof on the medicine.
2. in view of the multiformity of pharmaceutical preparation, drug regimen of the present invention is selected appropriate pharmaceutic adjuvant for use, Pharmaceutical composition can be processed dosage forms such as injectable powder, aqueous injection, capsule, tablet, granule.
3. the kind of pharmaceutic adjuvant and consumption are decided according to pharmaceutical dosage form, and the pharmaceutic adjuvant of selecting for use should be convenient to medication preparation, store, use and promote absorbing of main component interferon (IFNs) and its synergist.For example the PH buffer agent is selected citrate etc. for use, and excipient is selected mannitol, dextrin etc. for use, and binding agent is selected gelatin fiber element etc. for use, and stabilizing agent is selected glutamic acid, lysine, hetastarch etc. for use.
Description of drawings
Fig. 1 significantly increases I type interferon (the inductive reporter gene expression of IFN α/β) for the interferon synergist.(is example with Luteolin)
Fig. 1 explanation: (A) cell screening modelling verification, HepG2-ISRE-Luc2 cell add JAK inhibitor 1 earlier and handle the IFN α/β that adds 200U/mL after 2 hours again, and cell lysis detects uciferase activity after 24 hours.(B) luteolin (Luteolin) significantly increases I type interferon (the inductive reporter gene expression of IFN α/β).(C) synergism of JAK inhibitor 1 inhibition luteolin (Luteolin) and IFN α; The HepG2-ISRE-Luc2 cell adds JAK inhibitor 1 processing earlier and adds the IFN α of 200U/mL or the IFN α of luteolin (Luteolin) and 200U/mL again after 2 hours, and cell lysis detects uciferase activity after 24 hours.(D) the collaborative IFN α of luteolin (Luteolin) activates the ISRE reporter gene, and the HepG2-ISRE-Luc2 cell adds the luteolin (Luteolin) of variable concentrations and handles the IFN α that adds 200/mL after 2 hours again, and cell lysis detects uciferase activity after 24 hours.
Fig. 2 interferon synergist significantly increases the inductive JAK1 of I type interferon (IFN β), TYK2, STAT1, STAT2 phosphorylation level (is example with Luteolin).
Fig. 2 explanation: cracking behind IFN β (200U/mL) or 6 μ M Luteolin and IFN β (200U/mL) Combined Treatment HepG2 cell 10min, 30min, 1h, the 24h separately, WesternBlot detects the phosphorylation level of (A) anti-phospho-JAK1 (Tyr1022/1023) or anti-phospho-Tyk2 (Tyr1054/1055) antibody test JAK1 and TYK2.(B) tyrosine or the serine phosphorylation level of anti-phospho-STAT1 (Tyr701 or Ser727) or anti-STAT 1 antibody test STAT1.(C) the tyrosine phosphorylation level of anti-phospho-STAT2 (Tyr690) or anti-STAT2 antibody test STAT2.
Fig. 3 interferon synergist significantly increases the delay (with Luteolin is example) of the inductive STAT1 of I type interferon (IFN-β) in nucleus.
Fig. 3 explanation: the fluorescence inverted microscope is observed after adding (A), (B) DMSO or 2000U/mLIFN-β 1h behind the HepG2 cell transient transfection STAT1-GFP plasmid 24h.(C), the fluorescence inverted microscope is observed behind (D) 2000U/mL IFN-β or the 6 μ M Luteolin associating 2000U/mLIFN-β 24h.(E) behind the different disposal 24h STAT1 nucleus and cytoplasmic ratio (
*P＜0.05).
Fig. 4 interferon synergist significantly increases antiviral genes such as the inductive PKR of I type interferon (IFN-α), 2 ' 5 '-OAS and expresses (is example with Luteolin).
Fig. 4 explanation: (A) DMSO; Extract RNA behind IFN α (200U/mL) or 6 μ M Luteolin and IFN α (200U/mL) the Combined Treatment HepG2 cell 24h separately; Real time PCR detects the expression of antiviral genes such as PKR, 2 ' 5 '-OAS; The result representes that with the gene expression ratio of drug treating group and contrast (DMSO) processed group GAPDH is an internal control gene.(B) DMSO; Separately behind IFN α (200U/mL) or 6 μ M Luteolin and IFN α (200U/mL) the Combined Treatment HepG2 cell 24h; Cell lysis extracts total protein, and WesternBlot detects the expression of antiviral protein PKR, 2 ' 5 '-OAS, and GAPDH is confidential reference items.
The specific embodiment
Embodiment below in conjunction with concrete sets forth the present invention.Should be understood that these embodiment only are used to illustrate the present invention, and be not used for limiting scope of the present invention.
Get 3 * 10
4Ten thousand IU Intederon Alpha-2as and luteolin 3g; Pharmaceutic adjuvant is selected hetastarch, phosphate buffer for use; Add the suitable quantity of water dissolving; Regulate PH about 7.4; Refilter sterilization; Be distributed into 100 bottles, lyophilization rear seal-cover packing promptly makes every bottle of combination lyophilized injectable powder that contains Intederon Alpha-2a 3,000,000 IU and 30mg luteolin.
Embodiment 2 Quercetins (Quercetin) and Intederon Alpha-2a combination lyophilized injectable powder:
Get 3 * 10
4Ten thousand IU Intederon Alpha-2as and Quercetin 5g; Pharmaceutic adjuvant is selected hetastarch, phosphate buffer for use; Add the suitable quantity of water dissolving; Regulate PH about 7.4; Refilter sterilization; Be distributed into 100 bottles, lyophilization rear seal-cover packing, i.e. Zhi every bottle of combination lyophilized injectable powder that contains Intederon Alpha-2a 3,000,000 IU and 50mg Quercetin.
Embodiment 3: antiviral composition of medicine Function detection
1. luciferase reporter gene detects
(1) test method
PGL4.26-5 * ISRE plasmid transfection HepG2 cell, and with 300 μ g/ml Hygromycin B screening several weeks obtains the monoclonal cell of anti-Hygromycin B through limiting dilution assay, through each item index verification and called after HepG2-ISRE-Luc2.Test the same day, with 1 * 10
4The density of cells/well with the HepG2-ISRE-Luc2 cell inoculation in 96 orifice plates at CO
2The incubator overnight incubation, second day, add preceding 2 hours of interferon and add the testing compound pretreatment, be blank with DMSO, add IFN α/β after 2 hours, cell lysis and use Thermo Scientific after 24 hours
The multi-functional microplate reader of Flash detects uciferase activity.
(2) result of the test and discussion
The cell strain HepG2-ISRE-Luc2 of stable transfection PGL4.26-5 * ISRE plasmid shown in Figure 1A; (IFN α/β) significantly activates the expression of ISRE reporter gene to I type interferon; And this activation can suppress by the jak kinase inhibitor fully, proves the susceptiveness and the reliability of test model.With this model discrimination to the remarkable interferon-induced ISRE reporter gene expression of potentiation of flavonoid compound; Be representative (Figure 1B) wherein with luteolin (Luteolin); Potentiation to I type interferon (IFN α) shows significant concentration dependency effect (Fig. 1 C); And this synergistic function also can be suppressed (Fig. 1 D) by the jak kinase inhibitor, has hinted that luteolin (luteolin) is through participating in its synergistic function of regulation and control JAK-STAT signal path performance.
2. the immune marking (WesternBlot)
(1) test method
Interferon (IFN-β) or luteolin (luteolin) and interferon (IFN-β) are handled the HepG2 cell of different time; Clean one time with PBS earlier; 3.5cm small cell culture dish adds 100 μ l RIPA lysate (50mM Tris then; 5mM EDTA; 150mM NaCl; 1%NP40; 0.5%deoxycholic acid; 1mM sodium orthovanadate; 1mM sodium fluoride; 10 μ g/ml aprotinine, 10 μ g/ml leupeptin, 10 μ g/ml pepstatin 1mM PMSF; PH 7.5), cracking 30min on ice, 4 ℃ of centrifugal (10,000 * g) 10min.Get supernatant and add isopyknic 2 * electrophoresis sample loading buffer, boiling water boils 5min.SDS-PAGE glue (10-12%), the 180V electrophoresis, 40min, 200mA, nitrocellulose filter changes film 3h.5%BSA, room temperature sealing 3h, 4 ℃ of one anti-incubated overnight, room temperature, the two anti-3h of hatching, (NJ), (Bio-Rad, Hercules CA) carry out photodensitometry to Quantity One software for Amersham Bioscience, Piscataway with the ECL detection then.
(2) result of the test and discussion
For confirming that whether luteolin (luteolin) influences the activated JAK-STAT signal path of interferon (IFNs), has further detected the influence of luteolin (luteolin) to the phosphorylation level of crucial kinases and transcription factor in inductive this signal path of interferon (IFNs).(IFN-β) compares with independent interferon; Luteolin (luteolin) has significantly increased the inductive JAK1 of interferon (IFN-β); The kinase whose tyrosine phosphorylation level of TYK2 (Fig. 2 A); And tyrosine phosphorylation level (Fig. 2 B of STAT1 and STAT2 transcription factor; 2C), result of the test shows that the dephosphorylation process of the phosphorylated tyrosine that luteolin (luteolin) maybe be through suppressing inductive JAKs of interferon (IFNs) and STATs brings into play its synergistic function.
3. living cells fluorescent microscopic imaging
(1) test method
The HepG2 cell is inoculated in culture dish at the bottom of the 3.5cm glass; Adherent back transient transfection pEGFP-STAT1 plasmid; Express behind the 24h respectively with DMSO; 2000U/mlIFN- β or 6 μ Mluteolin and 2000U/mlIFN- β handle different time; Use fluorescence inverted microscope (NikonEclipseTi-E) observation then and with cold monochrome cameras (CoolSNAPHQ2; Photometrics; Tucson; USA) take a picture; Every ware selects 50 cells to use NIS-elementsadvancedresearchimagingsoftware(NikonChina; Shanghai China) calculates nucleus and cytoplasm fluorescence intensity.
(2) result of the test and discussion
Whether influence the activated transcription factor STAT1 of interferon (IFNs) to nuclear transport process for observing luteolin (luteolin); The plasmid of the fusion rotein of coding STAT1-GFP is arrived the HepG2 cell by transfection; And expression 24h; Shown in Fig. 3 A; Not adding the inductive matched group STAT1 of interferon (IFN β) mainly is distributed in the Cytoplasm; And the STAT1 of 2000U/mL interferon (IFN β) processing 1h mainly is distributed in the nucleus (Fig. 3 B), has proved the STAT1-GFP chimera correctness of expression that makes up.The processed group (Fig. 3 D) that adds 2000U/mL interferon (IFN β) behind luteolin (luteolin) the pretreatment 2h again; STAT1-GFP is significantly higher than the matched group (Fig. 3 E) that only adds DMSO and 2000U/mL interferon (IFN β) processing 24h in the ratio of nucleus and Cytoplasm distribution, and latter STAT1-GFP migrates out nucleus and redistributes in Cytoplasm (Fig. 3 C).Result of the test shows that luteolin (luteolin) can significantly increase the activated transcription factor STAT1 of interferon (IFNs) in endonuclear accumulation, prolongs interferon (IFNs) and induces the JAK-STAT signal to lead to activationary time, thereby bring into play its synergistic function.
4. real-time quantitative PCR (Real time PCR)
(1) test method
Interferon (IFN-β) or luteolin (luteolin) and interferon (IFN-β) are handled the HepG2 cell of different time, clean one time with PBS earlier, and every 3.5cm Tissue Culture Dish adds 1ml Trizol (Invitrogen), mixing, and room temperature leaves standstill 5min.Move in the 1.5ml centrifuge tube, add the 0.2ml chloroform, vibration 15s leaves standstill 3min on ice.4 ℃ centrifugal, and 12000g * 15min gets supernatant.Add the 0.5ml isopropyl alcohol, liquid mixing gently in will managing, room temperature leaves standstill 10min.4 ℃ centrifugal, and 12000g * 10min abandons supernatant.Add 1ml 75% ethanol, washing precipitation gently.4 ℃, 7500g * 5min abandons supernatant.Dry, add an amount of DEPC H20 dissolving (65 ℃ of short 10-15min of dissolving), get total RNA.Use SuperScriptIII reverse transcriptase (Invitrogen) and oligo (dT18) primer, synthetic cDNA gets equivalent cDNA and carries out Real time pcr amplification, and used PCR primer is seen table 1.
Table 1 PCR primer
| ?PKR?sense | 5’-GTTTGCTTCTCTGGCGGTCTT-3’ |
| ?PKR?antisense | 5’-GCCATTTCTTCTTCCCGTATCC-3’ |
| 2’5’-OAS?sense | 5’-AGGTGGTAAAGGGTGGCTCC-3’ |
| 2’5’-OAS?antisense | 5’-ACAACCAGGTCAGCGTCAGAT-3’ |
| GAPDH?sense | 5’-TGCACCACCAACTGCTTAGC-3’ |
| GAPDH?antisense | 5’-GGCATGGACTGTGGTCATGAG-3’ |
(2) result of the test and discussion
For observing the influence that antiviral gene that cyanidenon (luteolin) induces interferon (IFNs) is expressed; Having detected cyanidenon (luteolin) by RT-PCR induces two promoter regions to contain antiviral gene 2 ' the 5 '-oligoadenylatesynthetase(2 ' 5 ' of ISRE response element-OAS) and double-strandedRNA-activatedproteinkinase(PKR to interferon (IFN α)) the mRNA expression; As shown in Figure 4, compare processed group 2 ' 5 '-OAS of two hours of cyanidenon (luteolin) preliminary treatment with the control group of independent interferon (IFN α) and the PKR expression significantly increases.Result of the test shows that luteolin (luteolin) significantly increases the inductive endogenous antiviral gene of interferon (IFNs) and expresses, and hint luteolin (luteolin) is potentiation interferon (IFNs) antiviral effect significantly.
In sum; This laboratory is with the activated plain stimulation responses element of JAK-STAT signal path downstream disturbance (the Interferon Stimulated Response Element of interferon; ISRE) be regulating and controlling sequence; Made up sensitive stable cell screening platform based on luciferase reporter gene; Through screening natural product and synthesized micromolecule chemistry library, obtained to have the flavonoid compound that collaborative interferon (IFNs) activates JAK/STAT signal pathway downstream luciferase reporter gene.With luteolin (Luteolin) is representative; Through immunoblotting methods such as (WesternBlot); Be illustrated in luteolin among the human hepatoma cell line HepG2 (Luteolin) and can significantly strengthen the inductive STAT1 of interferon (IFN β), STAT2 and JAK1 kinases tyrosine phosphorylation, and increase the protein expression of STAT1.Find that through making up the STAT1-GFP fusion rotein luteolin (Luteolin) has significantly strengthened the beta induced delay of STAT1 in nucleus of IFN-.Reverse transcriptase polymerase chain reaction (RT-PCR) test shows that luteolin (Luteolin) significantly strengthens the expression of the inductive PKR of interferon IFN-α and 2 ' 5 '-OAS antiviral gene, shows the significantly potentiation I type interferon (antiviral effect of IFN α/β) of luteolin (luteolin).
In addition; Experiment shows; (luteolin) is similar for said flavone compound and luteolin; All can significantly strengthen the expression (table 2) of the inductive luciferase reporter gene of interferon IFN-α; (the antiviral composition of medicine of IFN α/β) antiviral effect, so said flavone compound and interferon (IFNs) can be used for the treatment of relevant disease to potentiation I type interferon.
The inductive luciferase reporter gene of the said flavone compound potentiation of table 2 IFN-α
*F.I.(Fold?Induction)：the?ratio?of?experimental?activity?to?control?activity.
Claims (5)
1. an antiviral composition of medicine is characterized in that: contain interferon and flavone compound.
2. antiviral composition of medicine according to claim 1 is characterized in that: described flavone compound has following general structure:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7Be respectively H or OR ' (R '=H, alkyl, sugar).
3. antiviral composition of medicine according to claim 1 is characterized in that: the proportion of composing of interferon and flavone compound is: per 1,000,000 IU interferon and the combination of 2-200mg flavone compound.
4. antiviral composition of medicine according to claim 1 is characterized in that: described flavone compound is one or more in the claim 2.
5. antiviral composition of medicine according to claim 1; It is characterized in that: described interferon comprises the interferon (IFNs) of the various molecular weight of producing through biological extraction or genetic engineering, also comprises all hypotypes of acceptable and trim thereof on the medicine.
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| CN107987112A (en) * | 2018-01-17 | 2018-05-04 | 天津科技大学 | A kind of preparation method of afzclin derivative |
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| CN107987112A (en) * | 2018-01-17 | 2018-05-04 | 天津科技大学 | A kind of preparation method of afzclin derivative |
| CN107987112B (en) * | 2018-01-17 | 2020-11-03 | 天津科技大学 | Preparation method of afzelin derivative |
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Application publication date: 20120208 |