CN103893172B - The application in preparing anti-HIV-1 virus drugs of a kind of antiviral compound - Google Patents
The application in preparing anti-HIV-1 virus drugs of a kind of antiviral compound Download PDFInfo
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- CN103893172B CN103893172B CN201410120259.XA CN201410120259A CN103893172B CN 103893172 B CN103893172 B CN 103893172B CN 201410120259 A CN201410120259 A CN 201410120259A CN 103893172 B CN103893172 B CN 103893172B
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Abstract
The present invention is claimed the application in preparing anti-HIV-1 virus drugs of a kind of antiviral compound, the structural formula of described antiviral compound shown in formula I:(Formulas I) X is O or S.Compound provided by the invention is respectively provided with good antivirus action, researches and develops the strong theoretical basis and practical basis that provide for further antiviral drugs, has important research and development value and development significance.
Description
Technical field
The present invention relates to a kind of new compound, more particularly, to a kind of antiviral compound and application thereof.
Background technology
HIV-1 virus is originally found and found in the U.S. in 1981, and by a series of unknown causes, after the syndrome appearance that cellular immunity deficiency is feature, research worker has started the searching to its etiology.Nineteen eighty-three France's research group, from the lymph node of a lymph enlargement syndrome patient, isolates HIV-1 virus.It is a kind of slow virus infecting human immune system's cell, the immunity of this viral subversive human body, causes that immune system loses resistance, and causes that various disease and cancer are able in human body and survive, thus causing acquired immune deficiency syndrome (AIDS) acquired immune deficiency syndrome (AIDS).At present, universal insufficient due to AIDS education, the HIV in the whole world is still in rising trend, especially enters the quick rise period especially in China.Acquired immune deficiency syndrome (AIDS) is stoped to become an instant major issue at the popular of China as early as possible.Therefore; continue to expand our understanding to HIV-1 mechanism of causing a disease; develop more effective; more economical; the antiviral drugs of less side effect replicates with the HIV-1 of fully erased remnants; and develop the vaccine of strong and long-acting anti-HIV-1 to protect Susceptible population, will be that can we finally defeat the key of acquired immune deficiency syndrome (AIDS).
Summary of the invention
The present invention provides the application in preparing anti-HIV-1 virus drugs of a kind of antiviral compound, the structural formula of described antiviral compound shown in formula I:
(Formulas I)
X is O or S.
Described antiviral compound includes the acceptable pharmaceutical salts of the compound described in Formulas I.
Described pharmaceutical salts is sodium salt, potassium salt or calcium salt.
The invention have the advantages that
Use HIV-1Vif albumen can pass through the functional characteristic of ubiquitination degraded A3G albumen, it was demonstrated that the antiviral compound of above-mentioned formula can suppress the activity of Vif protein degradation A3G, cause that the expression of screening system Green fluorescin will go up.Confirm by carrying out the infection experiment of wild type HIV-1 virus in the CD4+T lymphocyte series such as the primary CD4+T lymphocyte of people and H9, SupT1, they are respectively provided with good antivirus action, the strong theoretical basis provided for the research and development of further antiviral drugs and practical basis, have important research and development value and development significance.
Accompanying drawing explanation
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 suppressing Vif activity.
Fig. 4: antiviral compound is the print effect of suppression 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
The present invention is further described below in conjunction with specific embodiment.Unless stated otherwise, the present invention adopts reagent, equipment and method are the conventional commercial reagent of the art, equipment and conventional use of method.
Embodiment 1
Vif is one of indispensable protein of HIV, and its major function is antiviral agent APOBEC3G natural in antagonism host.APOBEC3G is that the one of HIV-1 virus threatens greatly, and it is present in host cell (such as CD4+T cell and macrophage) natural for HIV-1, can be wrapped into HIV-1 virion, play its extremely strong antivirus action in HIV-1 process of reverse-transcription.For this, HIV-1 self encodes Vif albumen and carrys out the antiviral activity of specificity antagonism APOBEC3G, and APOBEC3G can be imported ubiquitin system degraded (Fig. 1) by it.Therefore, how to inactivate Vif, be a highly important target of research and development anti-HIV-1 virus drugs.
Molecule mechanism according to Vif antagonism APOBEC3G, the Vif filtering out some HIV of allowing cannot degrade the small-molecule drug of APOBEC3G.For this, we will set up the living cells screening system of a kind of simplicity, as in figure 2 it is shown, by the plasmid co-transfection of expression APOBEC3G-GFP fusion protein and expression Vif to cell.So that whether APOBEC3G-GFP fusion protein is degraded to index.APOBEC3G-GFP fusion protein can also being made in case not to be degraded (namely GFP fluorescence also exists) as long as certain compound is deposited at Vif, 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 HIVVif albumen and express APOBEC3G(A3G) the plasmid co-transfection cell of-GFP fusion protein, VIF albumen can in conjunction with A3G-GFP, in combination with the protein complex E3 being made up of Cul5, EloB and EloC.E3 is a ubiquitination enzyme, can stamp ubiquitin label on A3G-GFP albumen, degrading thus mediating A3G-GFP entrance proteasome, causing not observing green fluorescence.
Fig. 2 is when adding after the compound library sieved, certain compound in storehouse inhibits the function of Vif, A3G-GFP fusion protein energy normal expression, and obvious green fluorescence be can be observed, this kind of compound is exactly Vif inhibitor, can be developed further into the lead compound for there being antiviral activity.
1) take cell strain 239t cell on well-grown people's kidney, be inoculated in 96 hole clear flat bottom plates, every hole 5 × 104 cell.The culture medium used is complete medium: DMEM in high glucose, 10% hyclone and 1% dual anti-, condition of culture be 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, transfects liquid 20 μ l.
3), after transfection 4h, compound to be screened is added, every hole 2 μ l, final concentration of 50 μMs.
4) after cultivating 48h, the expression of detection green fluorescent protein GFP.Express the situation risen if there is green fluorescent protein GFP, this compound is likely to become antiviral drug candidate.
Experimental result as it is shown on figure 3, from experimental result it can be seen that antiviral compound be respectively provided with suppress Vif activity effect.
Embodiment 2
Vif albumen has important function in HIV-1 virus replication, and the inhibition of HIV of vif defect can not replicate in CD4+T cell, macrophage, namely can not in above-mentioned " non-permitted " time multiplexed cell system；And the wild strain virus containing vif gene can in above-mentioned time multiplexed cell system.Reverse transcription can be carried out after Vif some target cell of gene-deleted strain cell entry, but proviral DNA can not be synthesized.Research display HIV replicates the appearance or disappearance put to death in a kind of cytostatic factor, this endogenic inhibitive factor is APOBEC3G, it belongs to intracellular rna editing enzymes, the cytosine deamination in mRNA can be made to form uracil, cause the accumulation of G and A mutant, and then be viral DNA degraded, vif forms the inhibitory activity of complex blocks APOBEC3G with APOBEC3G by being combined.In the APOBEC3G cell line such as H9 cell existed, APOBEC3G and vif protein binding is degraded by ubiquitination system, if compound can suppress APOBEC3G by vif protein degradation, host cell will not be able to be infected by HIV-1；And in APOBEC3G non-existent feelings cell line such as SupT1 cell, HIV-1 albumen can this host cell of normal infection；So this compound is it would be possible to become the compound of anti-HIV-1 Vif albumen.
APOBEC3G is the self-protective mechanism of cell, but vif is the albumen of HIV-1 virus countermeasure APOBEC3G function, causes oneself's reset procedure in HIV-1 viral escape cell.Utilize allowing cell and not allowing the effectiveness comparison of Antiviral breeding in cell of HIV-1, it is thus possible to determine that target compound can the Vif albumen of antagonism HIV-1 further in wild type Viral experiment, it is suppressed that the duplication that HIV-1 is viral.
1) taking well-grown lymphocyte series H9 and Supt1, cell consumption is 2 × 105/ hole, infects packaged HIV-1 viral supernatants respectively, and viral dose is 10ng/1 × 106Cell；(during infection, using short infection reagent polybrene)
2) change liquid after infecting 3h, use PBS 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, compound every hole 2 μ l(final concentration 50 μMs)；
3) use 2%TritonX-100 to process the supernatant receiving sample, receive the cell conditioned medium having cultivated 4day, survey P24Elisa.
Experimental result is as shown in Figure 4.From experimental result it can be seen that antiviral compound has good anti-HIV-1 virus function H9 cell, and there is no effect in SupT1 cell.
Embodiment 3
1) taking well-grown lymphocyte series H9, cell consumption is 2 × 105/ hole, infects packaged HIV-1 viral supernatants, and viral dose is 10ng/1 × 106Cell；(during infection, using short infection reagent polybrene)
2) change liquid after infecting 3h, use PBS 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 addition every hole 2 μ l of compound, final concentration respectively 50 μMs, 5 μMs, 0.5 μM, 0.05 μM, 0.005 μM, 0.0005 μM, 0 μM；
3) use 2%TritonX-100 to process the supernatant receiving sample, receive sample 4day, survey P24Elisa.
Experimental result is as shown in the table.From experimental result it can be seen that antiviral compound is respectively provided with the effect suppressing virus preferably.
Table 1 suppresses the effect of virus
Embodiment 4
MTS (3-(4,5-dimethylthiazol-2-yl)-5 (3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, innersalt) it is a kind of newly synthesized tetrazole compound, it is identical with the application principle of MTT, namely it is reduced into the viable count of each coloured first a ceremonial jade-ladle, used in libation product, its shade and some sensitive cells strain within the specific limits in height correlation by the multiple dehydrogenase in living cells mitochondrion.Absorbance (OD value) according to the 490n recorded, judges living cells quantity, and OD value is more big, and cytoactive is more strong, then it represents that drug toxicity is more little.
1) inoculating cell, is made into individual cells suspension with the DMEM culture fluid containing 10% tire calf serum by 293t, is inoculated into 96 orifice plates, every pore volume 200ul with 1000, every hole cell
2) 24h adherent after add compound, every hole 2 μ l, final concentration respectively 50 μMs, 5 μMs, 0.5 μM, 0.05 μM, 0.005 μM, 0.0005 μM, 0 μM
3) after cultivating 48h, every hole adds MTS solution 20ul, continues to hatch 2 ~ 4h in incubator
4) select 490nm wavelength, enzyme linked immunological monitor measures each hole absorbance value, observe the compound cytotoxicity to 293t cell.
Experimental result is as shown in table 2.From experimental result it can be seen that antiviral compound toxicity is relatively low, 293t cell is all rendered into acellular poison phenomenon.
Table 2 cytotoxicity experiment
| Compd. No. | X | CC50 (μM) |
| 1 | O | >50 |
| 2 | S | >50 |
The cytotoxicity of the compound of the present invention is relatively low.
Claims (1)
1. the antiviral compound application in preparing anti-HIV-1 virus drugs, it is characterised in that the structural formula of described antiviral compound shown in formula I:
X is O.
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Non-Patent Citations (2)
| Title |
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| Synthesis of some novel 2-substituted benzoxazoles as anticancer, antifungal, and antimicrobial agents;P.K.Jauhari, et al.;《MEDICINAL CHEMISTRY RESEARCH》;20080110;第17卷;第412-424页 * |
| Synthesis of some novel benzoxazole derivatives as anticancer,anti-HIV-1 and antimicrobial agents;Samia M. Rida, et al.;《European Journal of Medicinal Chemistry》;20050722;第40卷;第949-959页 * |
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