CN104130331A - Anti-HIV-1 drugs and preparation and application thereof - Google Patents
Anti-HIV-1 drugs and preparation and application thereof Download PDFInfo
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- CN104130331A CN104130331A CN201410275129.3A CN201410275129A CN104130331A CN 104130331 A CN104130331 A CN 104130331A CN 201410275129 A CN201410275129 A CN 201410275129A CN 104130331 A CN104130331 A CN 104130331A
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Abstract
The invention provides anti-HIV-1 drugs (also known as chimeric vectors Rev-Vif-C) prepared by splicing connection of Rev protein binding sites and a Vif protein C end, wherein the connection comprises substituting a Vif N end with Rev multimerization structural domains. In the study, the Rev-Vif-C vectors are designed and constructed, various experiments prove that the Rev-Vif-C vectors have a good anti-virus effect, and a new anti-virus technology aiming at an HIV-1 Rev protein is provided. The Vif-C vectors are successfully applied in degradation of the Rev protein, and are expected to become a novel gene knockout means. The Vif-C vectors can specifically degrade targeted proteins and are especially suitable for drug development of virus target proteins easy to produce high-frequency mutation, as long as the protein binding sites are not mutated, the chimeric vectors can be effective for a long term, and thus the drug resistance of the anti-virus drugs can be reduced.
Description
Technical field
The present invention relates to antiviral field, more specifically, relate to a kind of anti-HIV-1 virus drugs and preparation and application.
Background technology
At beginning of the eighties late 1970s, there is a kind of disease that function of immune system obstacle is principal character of take in Europe and the U.S..Subsequently, various countries scientist has just started seeking its pathogenesis and treatment plan.Until nineteen eighty-three, after French pasteur research group has successfully isolated this new retrovirus at first, people are also thereupon more and more for theoretical investigation and the therapeutic treatment of HIV-1.At present, for the drug main of HIV-l, will act on virus different links in life cycle, especially some necessary enzymes are as reversed transcriptive enzyme and proteolytic enzyme.
Although there is in the market the medicine of a lot of anti-HIV-1s, the widespread use of HARRT, the problems such as the resistance thereupon producing, huge medical expenses, Side effects of pharmaceutical drugs also should not be underestimated.Although HAART can make quite a few patient's plasma viral load be down to can detect below horizontal, after drug withdrawal, bounce-back and serious toxic side effect not yet can solve; Although gene therapy has shown its antiviral potentiality, and has part Study achievement to enter clinical experimental stage, the untoward reaction that its efficiency is low, foreign vector may bring etc. is still a major obstacle of research and development.At present, the research and development of anti-HIV-1 medicines mainly contain four focuses in the world: the one, enter cytostatics; The 2nd, neutralizing antibody; The 3rd, integrase inhibitor; The 4th, chemokine receptor antagonist.Scientists is still explored more safe and effective, applicable antiviral more economically keeping punching.
Virion protein expression regulatory factor Rev(regulation of virion protein expression) be indispensable modulin in HIV-1 transcription.The RRE of Rev and virus mRNA interacts, thereby helps the HIV-1 mRNA of not shearing or Partial Shear to transport outside core.If the expression of Rev is suppressed, the HIV-1 mRNA of montage or part montage can not transport and cause it degradable in core outside core, further block copying of HIV-1.Therefore, how to suppress the expression of Rev albumen, by an important target spot that is research and development anti-HIV-1 medicines.
Summary of the invention
The invention provides a kind of anti-HIV-1 virus drugs (having another name called chimeric vector Rev-Vif-C), described anti-HIV-1 virus drugs mainly for be the Rev albumen of HIV-1 self.
A kind of anti-HIV-1 virus drugs is provided in addition, and described anti-HIV-1 virus drugs is to be formed by connecting by Rev albumen and Vif albumen.
Described is connected to the N end of the multimerization structural domain replacement Vif of Rev.
The application of a kind of Vif albumen in preparing anti HIV-1 virus medicine is provided again.
The preparation method that a kind of above-mentioned anti-HIV-1 virus drugs is provided in addition, comprises the following steps:
S1. on the protein structure of Rev, there are two oligomerization domains, the 1-79 amino acids sequence of respectively these two oligomerization domains being replaced to Vif albumen n end, thereby three new chimeric protein ROL1-Vif-C, ROL2-Vif-C and ROL12-Vif-C have been built, described ROL1-Vif-C, the oligomerization domain that comprises Rev N end, the oligomerization domain that described ROL2-Vif-C comprises Rev C end, described ROL12-Vif-C comprises Rev N end and two oligomerization domains of C end
The oligomerization domain of described Rev N end is the 9-26 amino acids of Rev Argine Monohydrochloride sequence,
The oligomerization domain of described Rev C end is the 51-65 amino acids of Rev Argine Monohydrochloride sequence,
Described Rev N end and two 9-65 amino acids that oligomerization domain is Rev Argine Monohydrochloride sequence of C end.
Described Vif-C is partly the 80-193 amino acids of Vif Argine Monohydrochloride sequence
S2. these three chimeric vectors are cloned into respectively on expression vector pcDNA3.1, by transfection, carry out transient expression, wherein, in S1, shown in the described following SEQ NO:1 of 3 carrier sequences, SEQ NO:2 and SEQ NO:3, it is bamH I and Xhol I that carrier is connected to the upper restriction enzyme site used of pcDNA3.1.
According to above demand, provide three kinds of application, a kind of is the application of above-mentioned anti-HIV-1 virus drugs in preparing anti-HIV-1 medicines.
Another is the application of above-mentioned anti-HIV-1 virus drugs in preparing Inhibit the replication of HIV-1 medicine.
The application of a kind of above-mentioned anti-HIV-1 virus drugs in the Rev albumen of degraded HIV-1.
Vif albumen is an important albumen of HIV-1 self, can be in conjunction with target proteins, they are attached on an E3 ligase enzyme (ligase) mixture (Vif-SCF-CUL5 complex), then this mixture will make target proteins ubiquitination, thereby cause it at proteasome(proteasome) in degraded.The present invention is mainly according to the ubiquitination function of Vif albumen, the multimerization structural domain of Rev is replaced to the N end of Vif, can be specifically in conjunction with the Rev albumen of HIV-1, then by the ubiquitination function degraded Rev of Vif, lance with oneself is attacked own shield, thereby the order ground that reaches Inhibit the replication of HIV-1, has very strong novelty and specificity, this is also for research and development anti-HIV-1 medicines provides a kind of brand-new thinking and method.
(1) in order to overcome the shortcoming and deficiency of prior art, the object of the present invention is to provide a kind of method and the application in life science and clinical treatment thereof of structure of novel chimeric vector.
(2) the invention provides the new tool that a kind of Cell protection is not attacked by HIV-1; by the CD4+T cell sorting in patient body out after amplification in vitro; make its stably express Rev-Vif-C carrier; then feed back in patient body; not only can protect patient to avoid the attack again of HIV-1, can also assist patient to know the HIV-1 virus in body simultaneously.
(3) the present invention proposes a kind of novel vector of brand-new anti-HIV-1 spontaneous mutation---the resistance of HIV-1 is many because of its drug-induced self-break, and our chimeric vector is utilize mutually combining of Rev self structure territory and build, can avoid possible various sudden changes, thereby can have good inhibition to a plurality of HIV-1 mutant strains
(4) the present invention proposes a kind of new technology of the Rev of degraded protein expression
(5) the present invention proposes a kind of new technology of new degraded multiple protein---being combined into of certain albumen is a little inserted into the N end of Vif gene, thereby the ubiquitination path of holding by Vif C is realized the degradation process of specific proteins.
Accompanying drawing explanation
Fig. 1: the structure model of chimeric vector Rev-Vif-C.
Fig. 2: chimeric vector Rev-Vif-C is by ubiquitination path degraded Rev albumen.
Fig. 3: chimeric vector Rev-Vif-C suppresses copying of multiple wild-type HIV-1 virus strain by suppressing the kernel function that goes out of Rev-RRE.
Embodiment
Below in conjunction with the drawings and specific embodiments, further describe the present invention.Unless stated otherwise, reagent, equipment and the method that the present invention adopts is the conventional commercial reagent of the art, equipment and the conventional method of using.
The structure model of embodiment 1 chimeric vector Rev-Vif-C
Two oligomerization binding domainss (9-26 amino acids and 51-65 amino acid) on HIV-1 Rev gene are cloned into respectively to the N end of Vif gene, be substituted into the binding site (1-79 amino acids) of APOBEC3G, then be connected on the carrier of pcDNA3.1, formed 3 different chimeric, difference called after ROL1-Vif-C, ROL2-Vif-C, ROL12-Vif-C.Wherein ROL1 represents the oligomerization binding domains that the N end of Rev is divided, i.e. 9-26 amino acids; ROL2 represents the oligomerization binding domains that the C end of Rev is divided, i.e. 51-65 amino acids; The N end of ROL12 representative series connection Rev and two oligomerization binding domainss, i.e. 9-26 amino acids and 51-65 amino acids of C end.
Concrete steps are as follows:
(1) on the protein structure of Rev, there are two oligomerization domains, the 1-79 amino acids sequence of respectively these two oligomerization domains being replaced to Vif albumen n end, thereby three oligomerization domains that new chimeric protein ROL1-Vif-C(comprises Rev N end have been built, i.e. 9-26 amino acids), the oligomerization domain that ROL2-Vif-C(comprises Rev C end, i.e. 51-65 amino acids) and ROL12-Vif-C(comprises Rev N end and C holds two oligomerization domains, i.e. 9-65 amino acids)
(2) these three chimeric vectors are cloned into respectively to expression vector pcDNA3.1 above, by transfection, carry out transient expression
Wherein, in step (1), described vector construction comprises the following steps: according to the Vif albumen of HIV-1 and Rev albumen synthetic 4 pairs of primers respectively, the PNL4-3 plasmid sequence of HIV-1 virus of then take is template, utilizes above-mentioned primer to carry out pcr amplification; Then utilize different restriction enzyme sites that pcr amplification product is cloned into pcDNA3.1 above, wherein the fragment on position of Rev is at the N of Vif fragment end.
Embodiment 2 chimeric vector Rev-Vif-C are by ubiquitination path degraded Rev albumen
By HIV-1 Rev gene and RFP amalgamation and expression and be cloned on the carrier of pcDNA3.1, can reflect by observing the expression of RFP the expression of Rev like this; By Rev gene and HA label amalgamation and expression, conveniently do the expression that western blot further verifies Rev simultaneously.
(1) in the 293t of 24 orifice plates cell, cotransfection Rev-RFP and ROL1-Vif-C(or ROL2-Vif-C or ROL12-Vif-C) carrier, the amount of plasmid is respectively 1:0,1:1,1:2,1:3, after transfection 48h, observe the expression of RFP, simultaneously in the 293t of 6 orifice plates cell, cotransfection Rev-HA and ROL1-Vif-C carrier, the amount of plasmid is respectively 1:0,1:1,1:2,1:3, after transfection 48h, transfection is received lysis and is done the expression that Western Blot detects Rev
This description of test, three chimeric vectors can suppress the expression of Rev albumen, and have certain concentration gradient dependency.
(2), in the 293t of 24 orifice plates cell, cotransfection 200 ng Rev-RFP and 200 ng ROL12-Vif-C carriers, add the MG132 of 10 uM to process cell after 24 h, observe the expression of RFP after processing 12 h
(3) in the 293t of 24 orifice plates cell, cotransfection 200 ng Rev-RFP and 200 ng ROL12-Vif-C carriers, the si-NC of transfection 50 nM again after 6h, si-ElonginB, si-ElonginC and si-Culin5, observe the expression of RFP after transfection 48h
(4) in the 293t of 6cm plate cell, difference cotransfection 3 ug Ub-Flag, 3 ug Rev-HA and 2 ug ROL1-Vif-C, ROL2-Vif-C, ROL12-Vif-C carrier, receive lysis and do Co-IP enrichment Rev-HA albumen after transfection 48h, and further detect the ubiquitination situation of Rev albumen
Above three description of tests, chimeric vector is the ubiquitination path degraded Rev albumen mediating by Vif.
Embodiment 3 chimeric vector Rev-Vif-C suppress copying of multiple wild-type HIV-1 virus strain by suppressing the kernel function that goes out of Rev-RRE
On PDM628, have SD and SA shearing site, when Rev albumen does not exist, the luciferase gene carrying on PDM 628, by montage, causes luciferase trace expression; When two kinds of plasmid corotation, Rev and RRE combination, take luciferase gene fragment out of nucleus, avoids, by SD and SA montage, making luciferase great expression.Therefore, when Rev protein expression, receive while suppressing, Rev-RRE is relevant goes out nuclear translocation system and will be suppressed, and now the expression amount of luciferase will decline.Based on this principle, can judge whether the function of Rev albumen can be affected.
(1) in the 293t of 96 orifice plates cell, the Rev plasmid of difference cotransfection 10 ng pDM628 plasmids and 10 ng, and then the ROL1-Vif-C of cotransfection different concns, ROL2-Vif-C, ROL12-Vif-C and M10 plasmid, after transfection 48h, receive the expression that lysis detects luciferase
This description of test, three chimeric vectors can suppress the Rev-RRE nuclear translocation system of being correlated with out, and have certain concentration gradient dependency, and meanwhile, the effect of our chimeric vector will obviously be better than existing RevM10 mutant.
(2) in the 293t of 24 orifice plates cell, ROL1-Vif-C, ROL2-Vif-C, ROL12-Vif-C plasmid (50 ng of difference cotransfection 50 ng PNL4-3 plasmids and different concns, 100 ng, 150 ng), after transfection 48h, receive the expression (B) of supernatant ELISA detection P24 in the 293t of 24 orifice plates cell, ROL1-Vif-C, ROL2-Vif-C, ROL12-Vif-C plasmid (50 ng of difference cotransfection 50 ng PYU-2 plasmids and different concns, 100 ng, 150 ng), after transfection 48h, receive the expression that supernatant ELISA detects P24
This description of test, three chimeric vectors can suppress copying of multiple different wild-type HIV-1, and have certain concentration gradient dependency.
SEQUENCE LISTING
<110> Zhongshan University
<120> anti-HIV-1 virus drugs and preparation and application
<130>
<160> 3
<170> PatentIn version 3.3
<210> 1
<211> 537
<212> DNA
<213> ROL1-Vif-C
<400> 1
atggcaggaa gaagcggaga cagcgacgaa gagctcatca gaacagtcag actcatcaag 60
cttctctatc aaagcaaccc acctcccaac cccgagggga cccgacaggc ccgaaggaat 120
agaagaagaa ggtggagaga gagacagaga cagatccatt cgattagtga acggatcctt 180
ggcacttatc tgggacattt gggtcaggga gtctccatag aatggaggaa aaagagatat 240
agcacacaag tagaccctga actagcagac caactaattc atctgtatta ctttgactgt 300
ttttcagact ctgctataag aaaggcctta ttaggacaca tagttagccc taggtgtgaa 360
tatcaagcag gacataacaa ggtaggatct ctacaatact tggcactagc agcattaata 420
acaccaaaaa agataaagcc acctttgcct agtgttacga aactgacaga ggatagatgg 480
aacaagcccc agaagaccaa gggccacaga gggagccaca caatgaatgg acactag 537
<210> 2
<211> 405
<212> DNA
<213> ROL2-Vif-C
<400> 2
atggacagcg acgaagagct catcagaaca gtcagactca tcaagcttct ctatcaaagc 60
aaccatttgg gtcagggagt ctccatagaa tggaggaaaa agagatatag cacacaagta 120
gaccctgaac tagcagacca actaattcat ctgtattact ttgactgttt ttcagactct 180
gctataagaa aggccttatt aggacacata gttagcccta ggtgtgaata tcaagcagga 240
cataacaagg taggatctct acaatacttg gcactagcag cattaataac accaaaaaag 300
ataaagccac ctttgcctag tgttacgaaa ctgacagagg atagatggaa caagccccag 360
aagaccaagg gccacagagg gagccacaca atgaatggac actag 405
<210> 3
<211> 387
<212> DNA
<213> ROL12-Vif-C
<400> 3
atgatccatt cgattagtga acggatcctt ggcacttatc tgggacattt gggtcaggga 60
gtctccatag aatggaggaa aaagagatat agcacacaag tagaccctga actagcagac 120
caactaattc atctgtatta ctttgactgt ttttcagact ctgctataag aaaggcctta 180
ttaggacaca tagttagccc taggtgtgaa tatcaagcag gacataacaa ggtaggatct 240
ctacaatact tggcactagc agcattaata acaccaaaaa agataaagcc acctttgcct 300
agtgttacga aactgacaga ggatagatgg aacaagcccc agaagaccaa gggccacaga 360
gggagccaca caatgaatgg acactag 387
Claims (7)
1. an anti-HIV-1 virus drugs, is characterized in that, described anti-HIV-1 virus drugs is to be formed by connecting by Rev albumen and Vif albumen.
2. virus drugs according to claim 1, is characterized in that, described is connected to the N end of the multimerization structural domain replacement Vif of Rev.
3. the Vif albumen application in preparing anti-HIV-1 virus drugs.
4. a preparation method for anti-HIV-1 virus drugs, is characterized in that, comprises the following steps:
S1. on the protein structure of Rev, there are two oligomerization domains, the 1-79 amino acids sequence of respectively these two oligomerization domains being replaced to Vif albumen n end, thereby three new chimeric protein ROL1-Vif-C, ROL2-Vif-C and ROL12-Vif-C have been built, described ROL1-Vif-C, the oligomerization domain that comprises Rev N end, the oligomerization domain that described ROL2-Vif-C comprises Rev C end, described ROL12-Vif-C comprises Rev N end and two oligomerization domains of C end
The oligomerization domain of described Rev N end is the 9-26 amino acids of Rev Argine Monohydrochloride sequence,
The oligomerization domain of described Rev C end is the 51-65 amino acids of Rev Argine Monohydrochloride sequence,
Described Rev N end and two 9-65 amino acids that oligomerization domain is Rev Argine Monohydrochloride sequence of C end,
Described Vif-C is partly the 80-193 amino acids of Vif Argine Monohydrochloride sequence,
S2. these three chimeric vectors are cloned into respectively on expression vector pcDNA3.1, by transfection, carry out transient expression, wherein, in S1, shown in the described following SEQ NO:1 of 3 carrier sequences, SEQ NO:2 and SEQ NO:3, it is bamH I and Xhol I that carrier is connected to the upper restriction enzyme site used of pcDNA3.1.
5. the application of the anti-HIV-1 virus drugs described in a claim 1 or 2 in preparing anti-HIV-1 medicines.
6. the application of the anti-HIV-1 virus drugs described in a claim 1 or 2 in preparing Inhibit the replication of HIV-1 medicine.
7. the application of the anti-HIV-1 virus drugs described in a claim 1 or 2 in the Rev albumen of degraded HIV-1.
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| CN201410275129.3A CN104130331B (en) | 2014-06-19 | 2014-06-19 | A kind of virus drugs of AntiHIV1 RT activity 1 and its preparation and application |
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| CN201410275129.3A CN104130331B (en) | 2014-06-19 | 2014-06-19 | A kind of virus drugs of AntiHIV1 RT activity 1 and its preparation and application |
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| CN104130331A true CN104130331A (en) | 2014-11-05 |
| CN104130331B CN104130331B (en) | 2017-06-06 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1653085A (en) * | 2002-05-16 | 2005-08-10 | 巴法里安诺迪克有限公司 | Fusion protein of HIV regulatory/accessory proteins |
| US20110104789A1 (en) * | 2009-10-30 | 2011-05-05 | Yuntao Wu | Non-integrating rev-dependent lentiviral vector and methods of using the same |
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2014
- 2014-06-19 CN CN201410275129.3A patent/CN104130331B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1653085A (en) * | 2002-05-16 | 2005-08-10 | 巴法里安诺迪克有限公司 | Fusion protein of HIV regulatory/accessory proteins |
| US20110104789A1 (en) * | 2009-10-30 | 2011-05-05 | Yuntao Wu | Non-integrating rev-dependent lentiviral vector and methods of using the same |
Non-Patent Citations (4)
| Title |
|---|
| HIV-1病毒感染因子Vif 及其相关抑制剂的研究进展;李震宇等;《药学学报》;20100612;第45卷(第6期);摘要，第687页右栏第2段至第688页左栏第2段，第689页左栏第5段至右栏第1段，第692页左栏第2段 * |
| 一个新的HIV-1治疗靶点-Rev蛋白;叶英等;《药品评价》;20050426;第2卷(第2期);第108页右栏第2段至第109页左栏第1段，第109页左栏第4段至第110页右栏第1段 * |
| 叶英等: "一个新的HIV-1治疗靶点-Rev蛋白", 《药品评价》 * |
| 李震宇等: "HIV-1病毒感染因子Vif 及其相关抑制剂的研究进展", 《药学学报》 * |
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