CN103830232A - Application of antiviral compound in preparing anti-HIV-1 (Human Immunodeficiency Virus) medicine - Google Patents
Application of antiviral compound in preparing anti-HIV-1 (Human Immunodeficiency Virus) medicine Download PDFInfo
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Abstract
The invention discloses an application of an antiviral compound. The structural formula of the antiviral compound is shown in formula I in the specification. The compound disclosed by the invention has a good antiviral function, provides powerful theoretic basis and practical basis for development and research on antiviral medicines, and has great development and research values and development significance.
Description
Technical field
The present invention relates to a kind of new compound, more specifically, relate to a kind of antiviral compound and application thereof.
Background technology
HIV-1 virus is found at first 1981 and finds in the U.S., by a series of unknown causes, after the syndrome taking cellular immunity deficiency as feature occurs, research worker has started the searching to its etiology.Nineteen eighty-three France research group, from a lymph enlargement syndrome patient lymph node, is isolated HIV-1 virus.It is a kind of slow virus that infects human immunity system cells, this virus is destroyed the immunity of human body, cause immune system to lose resistance, and cause various diseases and cancer to be able to survive in human body, thereby cause acquired immune deficiency syndrome (AIDS)---acquired immune deficiency syndrome (AIDS).At present, universal insufficient due to AIDS education, the HIV in the whole world infects still in rising trend, has especially entered especially the rapid growth phase in China.Stop as early as possible acquired immune deficiency syndrome (AIDS) to become an instant major issue at China popular.Therefore; continue to expand our understanding to HIV-1 mechanism of causing a disease; develop more effective; more economical; still less the antiviral drugs of side effect copies to remove remaining HIV-1 completely; and the vaccine of developing strong and long-acting anti-HIV-1 is with protection Susceptible population, will be the key that can we finally defeat acquired immune deficiency syndrome (AIDS).
Summary of the invention
The invention provides a kind of antiviral compound in the application of preparing in anti-HIV-1 virus drugs, the structural formula of described antiviral compound is suc as formula shown in I:
Described R is 4-N (Me)
2, 4-N (Et)
2, 4-N (Pr)
2, 4-N (i-Pr)
2, 3-OH, 4-OMe, 2-OH, 4-N (Et)
2or
.
Provide a kind of antiviral compound in the application of preparing in anti-HIV-1 virus drugs, the structural formula of described antiviral compound is suc as formula shown in I again:
Described R is 3-OH and 4-OMe.
Provide a kind of antiviral compound in the application of preparing in anti-HIV-1 virus drugs, the structural formula of described antiviral compound is suc as formula shown in I:
Described R is 2-OH and 4-N (Et)
2.
Described antiviral compound also comprises the acceptable pharmaceutical salts of described compound.
Described pharmaceutical salts is sodium salt, potassium salt or calcium salt.
The present invention has the following advantages:
Use HIV-1 Vif albumen by the degrade functional characteristic of A3G albumen of ubiquitination, to confirm that the antiviral compound of above-mentioned general formula can suppress the activity of Vif protein degradation A3G, cause the expression of screening system Green fluorescin to go up.Confirm by the infection experiment that carries out wild type HIV-1 virus in CD4+ T lymphocyte series such as people's primary CD4+ T lymphocyte and H9, SupT 1 etc., they all have good antivirus action, research and develop for further antiviral drugs the strong theoretical basis and the practical basis that provide, there are important research and development and be worth and develop meaning.
Brief description of the drawings
Fig. 1 is the structure principle of cell screening model.
Fig. 2 is the structure principle of cell screening model.
Fig. 3: antiviral compound has the effect that suppresses Vif activity.
Fig. 4: antiviral compound suppresses the print effect of wild type HIV-1 in expressing the H9 cell of A3G albumen and not expressing the SupT1 cell of A3G albumen.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment.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 using.
Vif is one of indispensable protein of HIV, and its major function is antiviral agent APOBEC3G natural in antagonism host.APOBEC3G is that one of H IV-1 virus threatens greatly, and it is present in the natural host cell of HIV-1 (as CD4+ T cell and macrophage), can be wrapped the virion into HIV-1, brings into play its extremely strong antivirus action in HIV-1 reverse transcription process.For this reason, HIV-1 self the Vif albumen of having encoded carrys out the antiviral activity of specificity antagonism APOBEC3G, and it can import APOBEC3G ubiquitin system and degraded (Fig. 1).Therefore, how deactivation Vif, is a very important target of research and development anti-HIV-1 virus drugs.
According to the molecule mechanism of Vif antagonism APOBEC3G, the Vif that filters out some HIV of the allowing small-molecule drug of APOBEC3G of cannot degrading.We will set up a kind of easy living cells screening system for this reason, as shown in Figure 2, by the plasmid co-transfection of expressing APOBEC3G-GFP fusion rotein and express Vif in cell.Whether be degraded to index with APOBEC3G-GFP fusion rotein.As long as certain compound can also make APOBEC3G-GFP fusion rotein not be degraded (being that GFP fluorescence also exists) in the situation that Vif exists, this compound is exactly the inhibitor of Vif.By the further qualification to Vif target, confirm that compound acts on host cell or acts on the Vif of virus protein.
Fig. 1 will express the plasmid of HIV Vif albumen and express APOBEC3G(A3G) the plasmid co-transfection cell of-GFP fusion rotein, VIF albumen can be in conjunction with A3G-GFP, simultaneously in conjunction with the protein complex E3 being made up of Cul5, EloB and EloC.E3 is a ubiquitination enzyme, can on A3G-GFP albumen, stamp ubiquitin label, degrades thereby mediation A3G-GFP enters proteasome, causes not observing green fluorescence.
Fig. 2 is when adding after the compound library sieving, certain compound in storehouse has suppressed the function of Vif, and A3G-GFP fusion rotein energy normal expression, can be observed obvious green fluorescence, this kind of compound is exactly Vif inhibitor, can be developed further into the lead compound for there being antiviral activity.
1) get cell strain 239t cell on well-grown people's kidney, be inoculated in the 96 transparent flat undersides in hole every hole 5 × 104 cells.The culture medium using is complete medium: DMEM in high glucose, and 10% hyclone and 1% dual anti-, condition of culture is 5% carbon dioxide, 37 DEG C;
2) 24h adherent after, two kinds of plasmids of cotransfection PEGFP-A3G and pcDNA3.1-Vif.Transfection adopts liposome transfection, and reagent uses lipo2000, transfection liquid 20 μ l.
3) after transfection 4h, add compound to be screened, every hole 2 μ l, final concentration is 50 μ M.
4) cultivate after 48h, detect the expression of green fluorescent protein GFP.Express the situation rising if there is green fluorescent protein GFP, this compound may become antiviral drug candidate.
Experimental result as shown in Figure 3, can find out from experimental result, and antiviral compound all has the effect that suppresses Vif activity.
Embodiment 2
Vif albumen has important function in HIV-1 virus replication, and the HIV virus of vif defect can not copy in CD4+T cell, macrophage, can not be in above-mentioned " non-permission " time multiplexed cell system; And the wild strain virus that contains vif gene can be in above-mentioned time multiplexed cell system.After some target cell of Vif gene-deleted strain cell entry, reverse transcription can be carried out, but proviral DNA can not be synthesized.Studies show that HIV copies appearance or the disappearance of putting to death in a kind of cytostatic factor, this endogenic inhibitive factor is APOBEC3G, it belongs to intracellular rna editing enzymes, can make the cytosine deaminizating in mRNA form uracil, cause the accumulation of G and A mutant, and then be viral DNA degraded, vif forms the inhibition activity of complex blocking-up APOBEC3G by being combined with APOBEC3G.APOBEC3G exist cell line as H9 cell in, APOBEC3G and vif protein binding are degraded by ubiquitination system, if compound can suppress APOBEC3G by vif protein degradation, host cell can not be infected by HIV-1; And the non-existent feelings cell line of APOBEC3G as SupT1 cell in, HIV-1 albumen can normally infect this host cell; This compound will likely become the compound of anti-HIV-1 Vif albumen so.
APOBEC3G is the self-protective mechanism of cell, but vif is the albumen of HIV-1 virus antagonism APOBEC3G function, causes HIV-1 virus to escape self-reset procedure in cell.Utilize the permission cell of HIV-1 and do not allow the effect comparison of antiviral in cell experiment, thereby can further in wild type Viral experiment, determine the Vif albumen that target compound can antagonism HIV-1, suppress copying of HIV-1 virus.
1) get well-grown lymphocyte series H9 and Supt 1, cell consumption is 2 × 10
5/ hole, infects respectively packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 × 10
6cell; (when infection, using the short reagent polybrene that infects)
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, the every hole 2 μ l(final concentration 50 μ M of compound);
3) use 2%Triton-100 to process the supernatant of receiving sample, receive the cell conditioned medium of having cultivated 4day, survey P24 Elisa.
Experimental result as shown in Figure 4.Can find out from experimental result, antiviral compound has good anti-HIV-1 virus function in H9 cell, and there is no effect in SupT1 cell.
Embodiment 3
1) get well-grown lymphocyte series H9, cell consumption is 2 × 10
5/ hole, infects packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 × 10
6cell; (when infection, using the short reagent polybrene that infects)
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, add the every hole 2 μ l of compound, final concentration is respectively 50 μ M, 5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M, 0.0005 μ M, 0 μ M;
3) use 2%Triton-100 to process the supernatant of receiving sample, receive sample 4day, survey P24 Elisa.
Experimental result is as shown in the table.Can find out from experimental result, antiviral compound all has the viral effect of good inhibition.
Table 1 suppresses viral effect
MTS (3-(4,5-dimethylthiazol-2-yl)-5 (3-carboymethoyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt) be a kind of new synthetic tetrazole compound, it is identical with the application principle of MTT, be reduced into separately coloured first a ceremonial jade-ladle, used in libation product by the multiple dehydrogenase in living cells mitochondrion, the viable count of its shade and some sensitive cells strain is height correlation within the specific limits.According to the absorbance of the 490n recording (OD value), judge living cells quantity, OD value is larger, and cytoactive is stronger, represents that drug toxicity is less.
1) inoculating cell, uses containing the DMEM culture fluid of 10% tire calf serum 293t is made into individual cells suspension, is inoculated into 96 orifice plates, every pore volume 200ul with 1000, every hole cell
2) 24h adds compound after adherent, every hole 2 μ l, and final concentration is respectively 50 μ M, 5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M, 0.0005 μ M, 0 μ M
3) cultivate after 48h, every hole adds MTS solution 20ul, continues to hatch 2 ~ 4 h in incubator
4) select 490nm wavelength, on enzyme linked immunological monitor, measure each hole absorbance value, observe the cytotoxicity of compound to 293t cell.
Experimental result is as shown in table 2.Can find out from experimental result, antiviral compound toxicity is lower, is all ready-made acellular malicious phenomenon in 293t cell.
Table 2 cytotoxicity experiment
| Compd. No. | R | CC 50 ?(μM) a |
| 1 | 4-N(Me) 2 | >50 |
| 2 | 4-N(Et) 2 | >50 |
| 3 | 4-N(Pr) 2 | >50 |
| 4 | 4-N(i-Pr) 2 | >50 |
| 5 |
 |
>50 |
| 6 | 3-OH, 4-OMe | >50 |
| 7 | 2-OH, 4-N(Et) 2 | >50 |
The cytotoxicity of compound of the present invention is lower.
Claims (5)
1. antiviral compound, in an application of preparing in anti-HIV-1 virus drugs, is characterized in that, the structural formula of described antiviral compound is suc as formula shown in I:
Described R is 4-N (Me)
2, 4-N (Et)
2, 4-N (Pr)
2, 4-N (i-Pr)
2, 3-OH, 4-OMe, 2-OH, 4-N (Et)
2or
.
2. antiviral compound, in an application of preparing in anti-HIV-1 virus drugs, is characterized in that, the structural formula of described antiviral compound is suc as formula shown in I:
Described R is 3-OH and 4-OMe.
3. antiviral compound, in an application of preparing in anti-HIV-1 virus drugs, is characterized in that, the structural formula of described antiviral compound is suc as formula shown in I:
Described R is 2-OH and 4-N (Et)
2.
4. according to the arbitrary described application of claim 1 ~ 3, it is characterized in that, described antiviral compound also comprises the acceptable pharmaceutical salts of described compound.
5. application according to claim 4, is characterized in that, described pharmaceutical salts is sodium salt, potassium salt or calcium salt.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0444327A1 (en) * | 1990-03-01 | 1991-09-04 | Agfa-Gevaert N.V. | Dyes for use in thermal dye transfer |
| JPH041086A (en) * | 1990-04-19 | 1992-01-06 | Sankyo Kagaku Kk | Dye for thermal transfer recording |
| JPH0440429A (en) * | 1990-06-06 | 1992-02-10 | Toyobo Co Ltd | Nonlinear optical material |
| WO2006094235A1 (en) * | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Fused heterocyclic compounds and their use as sirtuin modulators |
| WO2011097607A1 (en) * | 2010-02-08 | 2011-08-11 | Southern Research Institute | Anti-viral treatment and assay to screen for anti-viral agent |
-
2014
- 2014-03-28 CN CN201410120209.1A patent/CN103830232B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0444327A1 (en) * | 1990-03-01 | 1991-09-04 | Agfa-Gevaert N.V. | Dyes for use in thermal dye transfer |
| JPH041086A (en) * | 1990-04-19 | 1992-01-06 | Sankyo Kagaku Kk | Dye for thermal transfer recording |
| JPH0440429A (en) * | 1990-06-06 | 1992-02-10 | Toyobo Co Ltd | Nonlinear optical material |
| WO2006094235A1 (en) * | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Fused heterocyclic compounds and their use as sirtuin modulators |
| WO2011097607A1 (en) * | 2010-02-08 | 2011-08-11 | Southern Research Institute | Anti-viral treatment and assay to screen for anti-viral agent |
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