CN111568902B - Application of 4- (4-chlorphenyl) -1H-pyrazole-5-amine and derivatives thereof in preparation of HIV-1 expression inhibitor - Google Patents
Application of 4- (4-chlorphenyl) -1H-pyrazole-5-amine and derivatives thereof in preparation of HIV-1 expression inhibitor Download PDFInfo
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- 241000713772 Human immunodeficiency virus 1 Species 0.000 title claims abstract description 46
- CTDDRNREDMYWMI-UHFFFAOYSA-N 4-(4-chlorophenyl)-1h-pyrazol-5-amine Chemical compound N1N=CC(C=2C=CC(Cl)=CC=2)=C1N CTDDRNREDMYWMI-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000003112 inhibitor Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 7
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- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 claims abstract description 19
- 230000007420 reactivation Effects 0.000 claims abstract description 17
- 230000004913 activation Effects 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
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- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
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- FXYZDFSNBBOHTA-UHFFFAOYSA-N 2-[amino(morpholin-4-ium-4-ylidene)methyl]guanidine;chloride Chemical compound Cl.NC(N)=NC(=N)N1CCOCC1 FXYZDFSNBBOHTA-UHFFFAOYSA-N 0.000 description 1
- -1 4- (4-chlorphenyl) -1H-pyrazole-5-amine (4- (4-chlorophenyl) -1H-pyrazol-5-amine) Chemical compound 0.000 description 1
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
The invention discloses application of bioactive molecules 4- (4-chlorphenyl) -1H-pyrazole-5-amine and derivatives thereof to an HIV-1 expression inhibitor. The invention discovers that 4- (4-chlorphenyl) -1H-pyrazole-5-amine has no obvious toxicity to cells in a wide drug concentration range, has the EC50 of HIV-1 as low as 23.26 mu M, and proves that the 4- (4-chlorphenyl) -1H-pyrazole-5-amine can be used as a reactivation inhibitor which is very safe, effective, broad-spectrum and specific for resisting HIV-1HIV-1 latent infection, thereby providing a novel target and a drug development direction for developing more antiviral drugs.
Description
Technical Field
The invention relates to a new application of a compound, in particular to an application of a bioactive molecule 4- (4-chlorphenyl) -1H-pyrazole-5-amine and a derivative thereof in HIV-1 expression inhibitors.
Background
Human immunodeficiency virus type I (HIV-1) is the causative agent of AIDS. Currently, the virus is suppressed mainly by combination antiviral therapy against HIV-1 infection. Because of the relatively short duration of this compression, patients need to take drugs for life. Once the drug action is stopped, viremia rapidly rebounds in a very short time. Most current antiviral drugs act directly on the virus. However, there are also numerous side effects. Moreover, none of these drugs can mobilize the intracellular immune system of the host cell to actively suppress the virus, nor can they permanently silence all integrated viruses. Scientists have proposed a variety of functional curative treatment strategies in succession, including "shock and kill" and "block and lock", among others. However, these strategies are still in the in vitro validation stage at present, and a large amount of clinical data indicate that no effective latent infection activator or latent infection permanent silencer can be well validated in clinical practice.
The LTR of HIV-1 is the location of the viral promoter. The mechanism research of HIV-1 latent infection shows that a large amount of inhibitory epigenetic modification on LTR can remarkably suppress the expression of HIV-1 and limit the reactivation of HIV-1. These modifications are mostly viral silencing caused by active attack of the host cell. Thus, sufficient mobilization of host intracellular immunity, acting directly on the LTR of HIV-1 would be expected to sufficiently turn on or permanently turn off HIV-1 expression. Meanwhile, by combining powerful and effective immune monitoring, a novel drug is developed to act on an HIV-1 promoter, so that the virus is expected to be fully activated and killed. For viruses that are difficult to activate, the virus can be permanently silenced by treatment with the compound. Whether activating or permanently silencing the virus, we are asked to develop new drugs.
The structural formula of 4- (4-chlorphenyl) -1H-pyrazole-5-amine (4- (4-chlorophenyl) -1H-pyrazol-5-amine) is as follows:
few inhibitors of LAP are currently reported, and the HIV-1 suppression effect of LAP inhibitors is much less observed. No research reports that 4- (4-chlorphenyl) -1H-pyrazole-5-amine has the related applications of resisting HIV-1 infection, treating and the like are currently reported.
Disclosure of Invention
The invention aims to provide application of 4- (4-chlorphenyl) -1H-pyrazol-5-amine as a low-toxicity and safe HIV-1 latent infection inhibitor.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
application of 4- (4-chlorphenyl) -1H-pyrazole-5-amine and derivatives thereof in preparing HIV-1 latent infection reactivation inhibitor.
Further, the reactivation of the above latent HIV-1 infection is mediated activation by a mediator.
Further, the above-mentioned mediating factor mediated activation is Tat factor mediated viral activation.
Further, the HIV-1 latent infection reactivation inhibitor comprises an effective dose of 4- (4-chlorophenyl) -1H-pyrazol-5-amine and derivatives thereof.
Furthermore, the HIV-1 latent infection reactivation inhibitor also comprises pharmaceutically acceptable auxiliary materials.
Further, the HIV-1 latent infection reactivation inhibitor is an oral preparation or an injectable preparation.
Furthermore, the oral preparation is tablet, capsule and granule; the injection preparation is injection or powder injection.
Furthermore, the HIV-1 latent infection reactivation inhibitor consists of 10-90% of 4- (4-chlorphenyl) -1H-pyrazole-5-amine and derivatives thereof and 10-90% of pharmaceutically acceptable auxiliary materials.
The invention has the beneficial effects that:
the invention discovers that 4- (4-chlorphenyl) -1H-pyrazole-5-amine has no obvious toxicity to cells in a wide drug concentration range, and the EC50 of the 4- (4-chlorphenyl) -1H-pyrazole-5-amine is as low as 23.26 mu M to HIV-1, thereby proving that the 4- (4-chlorphenyl) -1H-pyrazole-5-amine is used as a reactivation inhibitor which is very safe, effective, broad-spectrum and specific to resist HIV-1HIV-1 latent infection, and providing a novel target point and a drug development direction for developing more antiviral drugs.
Drawings
FIG. 1 is a graph of the inhibition of GFP expression driven by the HIV-1 promoter of latent infection by bioactive molecular compounds in a pool of bioactive molecular compounds;
FIG. 2 is a graph showing the effect of 4- (4-chlorophenyl) -1H-pyrazol-5-amine on inhibition of HIV-1 viral protein Tat-mediated viral expression in a cell line latently infected with HIV-1;
FIG. 3 is a graph showing the toxic effect of 4- (4-chlorophenyl) -1H-pyrazol-5-amine in HIV-1 latently infected cells;
FIG. 4 is a graph showing the suppression of HIV-1 by 4- (4-chlorophenyl) -1H-pyrazol-5-amine in HIV-1 latently infected cells;
FIG. 5 is a graph showing the concentration of 4- (4-chlorophenyl) -1H-pyrazol-5-amine effective for inhibiting HIV-1 expression.
Detailed Description
The invention will be described in further detail with reference to the drawings and specific experiments. The experimental procedures and drawings are only for explaining the present invention and are not intended to limit the scope of the present invention. The experimental methods used in the implementation are all conventional experimental methods if not specifically stated.
The experimental materials and reagents used are, unless otherwise specified, all consumables and reagents which are conventionally available from commercial sources.
The specific experimental method comprises the following steps:
1) well-grown J-Lat 10.6 cells were plated evenly in 96-well plates using the following culture conditions: RPMI1640, 10% FBS, 1% double antibody, 5% CO2Culturing at 37 deg.C for 24 hr;
2) after 24 hours of cell culture, cells were stimulated with 0.02mg/μ l Tat for activation of latently infected HIV-1 for 12 hours;
3) after the cells are cultured for 12 hours, adding a bioactive molecule library compound into each corresponding hole, wherein the negative control uses the same amount of DMSO, and culturing for 24 hours;
4) after the cells were further cultured for 24 hours, the cells were pipetted into a 1.5ml tube and centrifuged at 500G for 5 minutes at room temperature;
5) remove the medium supernatant, add 1ml of PBS to resuspend the cells, centrifuge again for 5 minutes, remove the PBS supernatant, and resuspend the cells with 500 μ Ι _ of PBS;
6) analyzing each compound-treated sample with a flow cytometer, wherein FSC and SSC are used to circle out valid viable cells and FITC is used to circle out activated HIV-1 infected cells;
7) the proportion of GFP expression of the negative control DMSO group is used as a Mock group, and the activation percentage of other groups relative to the activation multiple of the Mock group is calculated and subjected to histogram analysis.
The experimental results are as follows:
the results of the experiment are shown in FIG. 1. Various bioactive molecules have an inhibiting effect on HIV-1, wherein 4- (4-chlorphenyl) -1H-pyrazol-5-amine has a very obvious effect on antagonizing reactivation of HIV-1 latent infection, and the inhibiting effect is as high as more than 90%.
Experiment 2, 4- (4-chlorophenyl) -1H-pyrazol-5-amine specifically inhibits the activity of the HIV-1 promoter
The specific experimental method comprises the following steps:
1) HIV-1 expressing cell lines of TZM-bl were plated evenly in 24-well plates under the following culture conditions: culturing in DMEM, 10% FBS, 1% double antibody, 37 deg.C, 5% CO2 for 24 hr;
2) after 24 hours of cell culture, transfecting the Tat expression plasmid or empty vector into TZM-bl cells corresponding to each well with a liposome;
3) after 12 hours of transfection, the culture supernatant was removed and an equal volume of fresh DMEM was added, followed by 20 μ M of 4- (4-chlorophenyl) -1H-pyrazol-5-amine in one Tat-transfected well and one empty-transfected well, respectively, and an equal volume of DMSO in the remaining two groups of corresponding wells, respectively, and further incubation for 24 hours;
4) after the cells were cultured for a second 24 hours, the culture medium supernatant was removed and washed once in the wells with PBS, completely removing the PBS wash;
5) adding 100 μ L of cell lysate to each well, and performing shaking lysis at 220rpm for 30 minutes;
6) transfer the lysis supernatant to a 1.5ml tube, centrifuge at 12000rpm for 3 minutes, transfer the supernatant to a new 1.5ml tube;
7) 20 μ L of cell lysis supernatant was taken to a 96-well white plate and the Luciferase reporter system was used to determine the Luciferase content in each well, expressed as absorbance values for each group.
The experimental results are as follows:
the results of the experiment are shown in FIG. 2. The transfected virus Tat protein can obviously increase the expression of HIV-1 driven Luciferase, and Tat-mediated trans-activation of HIV-1 is obviously suppressed after cells are treated by 4- (4-chlorphenyl) -1H-pyrazol-5-amine, which indicates that 4- (4-chlorphenyl) -1H-pyrazol-5-amine has obvious suppression effect on an integrated HIV-1 promoter.
EXPERIMENT 3-HERBAL-1-INFECTIVE CELL TOLERANCE OF 4- (4-CHLOROPHENYL) -1H-PYRAZOL-5-AMINE
The specific experimental method comprises the following steps:
1) the HIV-1 pseudovirus latent infection cell line J-Lat is evenly paved in a 24-well plate, and the culture conditions are as follows: culturing in RPMI1640, 10% fetal calf serum, 1% double antibody, 5% CO2 at 37 deg.C for 24 hr;
2) after 24 hours of cell culture, Tat was added to each well so that the final concentration was 0.02mg/μ l, and cultured for 12 hours;
3) after further culturing of the cells for 12 hours, the following concentration gradient of 4- (4-chlorophenyl) -1H-pyrazol-5-amine was added to each well: 160. mu.M, 80. mu.M, 40. mu.M, 20. mu.M, 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M, 0.625. mu.M and 0. mu.M;
4) after 24 hours of drug treatment, cells were resuspended and transferred to 1.5ml tubes, after centrifugation at 500G for 5 minutes, rinsed once with PBS, followed by resuspension of cells with 100 μ Ι of PBS and addition of 1 μ Ι of PE-coupled dead/live cell dye;
5) cell staining for 30 min, vortex once every 10 min, centrifuge for 5 min at 500G, remove supernatant completely, add 1ml PBS and rinse once;
6) the cell pellet was resuspended in 300. mu.l of PBS and the proportion of dead and live cells was analyzed by flow cytometry, where PE positive cells were live cells.
The experimental results are as follows:
the results of the experiment are shown in FIG. 3. There was no significant change in cell viability at any concentration gradient, although at higher concentrations there was a slight decrease in the proportion of viable cells, indicating that J-Lat cells were well tolerated by the treatment with 4- (4-chlorophenyl) -1H-pyrazol-5-amine.
EXPERIMENT 4, semi-potent inhibitory concentration of 4- (4-chlorophenyl) -1H-pyrazol-5-amine
The specific experimental method comprises the following steps:
1) procedure 1) to procedure 3) as shown in experiment 3), cells were plated on 24-well plates and treated with Tat and drugs of different concentration gradients for 24 hours;
2) after 24 hours of drug treatment, cells were resuspended and transferred to a 1.5ml tube, centrifuged at 500G for 5 minutes, and the medium supernatant was removed thoroughly;
3) resuspend cells with 1ml PBS, centrifuge again at 500G for 5 min, then resuspend cells with 500 μ Ι PBS;
4) the cell suspension was analyzed by flow cytometry, viable cells were delineated by FSC and SSC, GFP-positive viable cells were indicated by FITC, the percentage of GFP-positive cells in each group was curve-fitted by statistical methods, and the concentration of 4- (4-chlorophenyl) -1H-pyrazol-5-amine at which it inhibits J-Lat cells semi-effectively was calculated.
The experimental results are as follows:
the results of the experiment are shown in fig. 4 and 5. The semi-effective concentration EC50 for inhibiting the reactivation of HIV-1 latently infected cells of 4- (4-chlorophenyl) -1H-pyrazol-5-amine was 23.26. mu.M, indicating that only a very small amount of 4- (4-chlorophenyl) -1H-pyrazol-5-amine was required to inhibit the reactivation of HIV-1. Also shows that the 4- (4-chlorphenyl) -1H-pyrazole-5-amine is a safe, effective and specific bioactive molecule and can be used for improving novel antiviral drugs.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (3)
- Application of 4- (4-chlorphenyl) -1H-pyrazole-5-amine in preparing HIV-1 latent infection reactivation inhibitor;the reactivation of HIV-1 latent infection is Tat factor mediated viral activation;the HIV-1 latent infection reactivation inhibitor consists of 10-90% of 4- (4-chlorphenyl) -1H-pyrazole-5-amine and 10-90% of pharmaceutically acceptable auxiliary materials.
- 2. The use according to claim 1, wherein the HIV-1 latent infection reactivation inhibitor is in an oral formulation or an injectable formulation.
- 3. The use according to claim 2, wherein the oral formulation is a tablet, capsule, granule; the injection preparation is injection or powder injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104013626A (en) * | 2014-05-28 | 2014-09-03 | 中山大学 | Application of pyridine-piperazine compounds to prepare anti-HIV-1 medicines |
| CN104013616A (en) * | 2014-05-28 | 2014-09-03 | 中山大学 | Application of acylamino-thiophene compounds to prepare anti-HIV-1 medicines |
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| CN104013626A (en) * | 2014-05-28 | 2014-09-03 | 中山大学 | Application of pyridine-piperazine compounds to prepare anti-HIV-1 medicines |
| CN104013616A (en) * | 2014-05-28 | 2014-09-03 | 中山大学 | Application of acylamino-thiophene compounds to prepare anti-HIV-1 medicines |
Non-Patent Citations (1)
| Title |
|---|
| Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching;Shidong Chu等;《Bioorganic & Medicinal Chemistry Letters》;20130722;第23卷;第5114-5118页 * |
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