CN104138373A - Application of hydroxy pyrithione salt in preparation of anti human herpes simplex virus (HSV) drug - Google Patents
Application of hydroxy pyrithione salt in preparation of anti human herpes simplex virus (HSV) drug Download PDFInfo
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- CN104138373A CN104138373A CN201310164880.1A CN201310164880A CN104138373A CN 104138373 A CN104138373 A CN 104138373A CN 201310164880 A CN201310164880 A CN 201310164880A CN 104138373 A CN104138373 A CN 104138373A
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Abstract
本发明属于制药领域，涉及羟基吡啶硫酮盐在制备抗人单纯疱疹病毒的药物中的应用。本发明发现羟基吡啶硫酮盐在体外实验中具有很强的抗人单纯疱疹病毒I型和II型的功能，能够抑制病毒晚期胞膜蛋白gD的mRNA的转录水平和蛋白表达水平。对羟基吡啶硫酮盐的体外毒性实验发现，该化合物对人和非洲绿猴的细胞具有较低的毒性，可以获得较高的治疗指数。因此，羟基吡啶硫酮盐具有作为一种新型抗HSV药物的潜在价值，可在制备抗人单纯疱疹病毒的药物中的应用。
The invention belongs to the field of pharmacy and relates to the application of pyrithione salt in the preparation of medicines against human herpes simplex virus. The present invention finds that the pyrithione salt has strong anti-human herpes simplex virus type I and type II functions in vitro experiments, and can inhibit the mRNA transcription level and protein expression level of the late virus membrane protein gD. The in vitro toxicity test of pyrithione salts found that the compound has low toxicity to human and African green monkey cells, and can obtain a high therapeutic index. Therefore, the pyrithione salt has potential value as a novel anti-HSV drug, and can be used in the preparation of anti-human herpes simplex virus drugs.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the application of pyrithione salts in the medicine of the anti-human herpes simplex virus of preparation.
Background technology
(pyrithione, also referred to as 1 hydroxyl-pyrithione for pyrithione; 2-pyridine mercaptan-1 oxide; Pyrithione; 2-mercaptopyridine-N_ oxide; Pyrithione; And pyrithione) multivalent metal salt is a kind of efficient zinc ion carrier, it carrys out chelated zinc ion by Yang Liu center, for effective antibacterial, the growth of Gram-positive and negative bacteria and mycete be can effectively suppress, and antifungal and the antibacterial of paint and metal working fluid are widely used as.Once had report abroad, pyrithione salts is inhibited to copying of ERC group virus, its virus of Ke's Sa and encephalomyocardis virus, and these three kinds of viruses all belong to Picornavirus.Have not yet to see the relevant report about the anti-human herpes simplex virus of pyrithione salts (HSV).
Summary of the invention
The object of the invention is the above-mentioned deficiency for prior art, the application of pyrithione salts in the anti-HSV of preparation is provided.
Object of the present invention can be achieved through the following technical solutions:
The application of pyrithione salts in the medicine of the anti-human herpes simplex virus of preparation (HSV).
Described pyrithione salts be selected from sodium pyrithione, ZPT, pyrithione barium, pyrithione bismuth, pyrithione strontium, copper pyrithion, pyrithione cadmium or copper pyrithion any one or multiple.
Described anti-human herpes simplex virus is herpes simplex virus I-type or herpes simplex virus type II.
Beneficial effect:
The present invention finds that pyrithione salts has the function of very strong anti-human herpes simplex virus I-type and II type (HSV-1 and HSV-2) in testing in vitro, can suppress transcriptional level and the protein expression level of the mRNA of virus membrane-associated protein gD in late period.To the in vitro toxicity experiment discovery of pyrithione salts, this compound has lower toxicity to the cell of people and cercopithecus aethiops, can obtain higher therapeutic index.Therefore, pyrithione salts has the potential value as a kind of novel anti-HSV medicine, can preparation anti-human herpes simplex virus medicine in application.
Accompanying drawing explanation
Fig. 1 sodium pyrithione suppresses HSV-1 and the infection of HSV-2 to HEC-1-A cell
Fig. 2 sodium pyrithione suppresses HSV-1 and the infection of HSV-2 to Hela cell
Fig. 3 sodium pyrithione suppresses HSV-1 and the infection of HSV-2 to Vero cell
Fig. 4 sodium pyrithione suppresses the formation of HSV-2 viral infection granule
The mRNA's of Fig. 5 sodium pyrithione inhibition HSV-2 virus gD albumen is synthetic
Fig. 6 sodium pyrithione is to several human cell line toxicity
The specific embodiment
Embodiment 1
HEC-1-A cell is inoculated in 96 porocyte culture plates, after cell converges, the sodium pyrithione that adds variable concentrations, foster 30min for 37 ℃, and virus titer MOI=1 is infected in postoperative infection HSV-1HF strain and HSV-2G strain (HSV-1HF strain and HSV-2G strain are all purchased from US mode culture collection warehousing (ATCC)).After 24hrs, discard culture medium, 4% paraformaldehyde is 15min fixedly, then utilizes 0.1%TritonX-100 to carry out breakthrough process, and totally 5 times, each 5min.Penetrate after end, utilize 4% defatted milk powder sealing 90min, after foster primary antibodie (gD and β-catenin, 1:200) 2hr.PBST buffer is washed plate 5 times, and each 5min fosters two anti-(Dylight800goat-anti-mouse and Dylight680goat-anti-rabbit, 1:1500) 1hr.PBST buffer detects in Odyseey Infrared Image System after washing plate.
Utilize In-cell Western method detect sodium pyrithione suppress HSV-1 and HSV-2 to people HEC-1-A cell (purchased from Chinese Academy of Sciences's cell bank, infection (content of virus envelope protein gD is directly proportional to newborn virus replication efficiency) down together), finds that it has obvious inhibition (see figure 1).
Embodiment 2
Hela cell is inoculated in 96 porocyte culture plates, after cell converges, adds the sodium pyrithione of variable concentrations, foster 30min for 37 ℃, and virus titer MOI=1 is infected in postoperative infection HSV-1HF strain and HSV-2G strain.After 24hrs, discard culture medium, 4% paraformaldehyde is 15min fixedly, then utilizes 0.1%TritonX-100 to carry out breakthrough process, and totally 5 times, each 5min.Penetrate after end, utilize 4% defatted milk powder sealing 90min, after foster primary antibodie (gD and β-catenin, 1:200) 2hr.PBST buffer is washed plate 5 times, and each 5min fosters two anti-(Dylight800goat-anti-mouse and Dylight680goat-anti-rabbit, 1:1500) 1hr.PBST buffer detects in Odyseey Infrared Image System after washing plate.
(infection of (purchased from Chinese Academy of Sciences's cell bank, lower same), finds that it has obvious inhibition (see figure 2) to Hela cell to utilize In-cell Western method detection sodium pyrithione inhibition HSV-1 and HSV-2.
Embodiment 3
Vero cell is inoculated in 96 porocyte culture plates, after cell converges, adds the sodium pyrithione of variable concentrations, foster 30min for 37 ℃, and virus titer MOI=1 is infected in postoperative infection HSV-1HF strain and HSV-2G strain.After 24hrs, discard culture medium, 4% paraformaldehyde is 15min fixedly, then utilizes 0.1%TritonX-100 to carry out breakthrough process, and totally 5 times, each 5min.Penetrate after end, utilize 4% defatted milk powder sealing 90min, after foster primary antibodie (gD and β-catenin, 1:200) 2hr.PBST buffer is washed plate 5 times, and each 5min fosters two anti-(Dylight800goat-anti-mouse and Dylight680goat-anti-rabbit, 1:1500) 1hr.PBST buffer detects in Odyseey Infrared Image System after washing plate.
Utilize In-cell Western method to detect sodium pyrithione and suppress HSV-1 and the infection of HSV-2 to African green monkey kidney cell Vero cell (purchased from Chinese Academy of Sciences's cell bank, lower same), find that it has obvious inhibition (see figure 3).
Embodiment 4
HEC-1-A cell is inoculated in 96 porocyte culture plates, after cell converges, adds the sodium pyrithione of variable concentrations, foster 30min for 37 ℃, and virus titer MOI=1 is infected in postoperative infection HSV-1HF strain and HSV-2G strain.After 24hrs, discard culture medium, add 200 μ l fresh cultures, then-20-37 ℃ multigelation 3 times, releasing virus particle.Vero-ICP10P cell is inoculated in to 96 orifice plates, after converging, adds the above-mentioned virion culture medium that contains of 50 μ l to join in hole, after 24hr, detect Luciferase activity.
The HEC-1-A cell being infected by HSV-2 that utilizes Vero-ICP0P cell detection sodium pyrithione to process, finds that sodium pyrithione is for the inhibited (see figure 4) of formation of the newborn viral infection granule of HSV-2 in cell.
Embodiment 5
HEC-1-A cell is inoculated in 24 porocyte culture plates, after cell converges, adds the sodium pyrithione of variable concentrations, foster 30min for 37 ℃, and virus titer MOI=1 is infected in postoperative infection HSV-2G strain.After 24hrs, discard culture medium, add 300 μ l Trizol cell lysis, the step of narrating in by specification is extracted cell total rna.Utilize the explanation of TOYOBO reverse transcription test kit, carry out the synthetic of cDNA the first chain.After carry out Realtime detection, adopt SYBR Green method, HSV-2gD forward primer is: CCAAATACGCCTTAGCAGACC, HSV-2gD downstream primer is: CACAGTGATCGGGATGCTGG; Internal reference is GAPDH, and GAPDH forward primer is: TGCACCACCAACTGCTTAGC, and GAPDH downstream primer is: GGCATGGACTGTGGTCATGAG; Reaction system 20 μ l, reaction condition is 95 ℃ of denaturations, 10min; 95 ℃, 15s, 60 ℃, 1min, totally 40 circulations, the extension stage is detected fluorescence.
Utilize Realtime-PCR technology for detection sodium pyrithione to suppress the infection of HSV-2 to HEC-1-A cell, find that its this compound has very strong inhibitory action (see figure 5) to the mRNA of HSV-2 virus gD albumen synthetic.
Embodiment 6
HEC-1-A, Hela or Vero cell are inoculated in 96 porocyte culture plates, after cell converges, add the sodium pyrithione of variable concentrations, foster 24hr for 37 ℃; Then add 10ulCCK-8 working solution, foster 2hr for 37 ℃, in 460nm, detect light absorption value.
Utilize CCK-8 method to detect the toxicity of sodium pyrithione to relevant cell strain, 3 strain cell strains are respectively human cervical carcinoma's epithelial cell Hela, people's endometrium endotheliocyte HEC-1-A and African green monkey kidney cell Vero, find its under effective antiviral concentration to cell without overt toxicity (see figure 6).
Claims (3)
1. the application of pyrithione salts in the medicine of the anti-human herpes simplex virus of preparation.
2. application according to claim 1, it is characterized in that described pyrithione salts be selected from sodium pyrithione, ZPT, pyrithione barium, pyrithione bismuth, pyrithione strontium, copper pyrithion, pyrithione cadmium or copper pyrithion any one or multiple.
3. application according to claim 1, is characterized in that described anti-human herpes simplex virus is herpes simplex virus I-type or herpes simplex virus type II.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018154601A (en) * | 2017-03-21 | 2018-10-04 | 日本曹達株式会社 | Antiviral agent and use therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283996A (en) * | 1997-10-28 | 2001-02-14 | 温斯洛普大学医院 | Method/thiol biochdes |
| CN1651640A (en) * | 2004-02-02 | 2005-08-10 | 大阪化成株式会社 | Process for preparing antibacterial, antifungal and antiviral fibers |
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- 2013-05-07 CN CN201310164880.1A patent/CN104138373A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283996A (en) * | 1997-10-28 | 2001-02-14 | 温斯洛普大学医院 | Method/thiol biochdes |
| CN1651640A (en) * | 2004-02-02 | 2005-08-10 | 大阪化成株式会社 | Process for preparing antibacterial, antifungal and antiviral fibers |
| CN101619539A (en) * | 2004-02-02 | 2010-01-06 | 大阪化成株式会社 | Method for producing bacteria, fungus and virus resisting fiber |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018154601A (en) * | 2017-03-21 | 2018-10-04 | 日本曹達株式会社 | Antiviral agent and use therefor |
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Application publication date: 20141112 |