CN111686107B - New application of compound PLX51107 in preparation of drug for preventing or treating African swine fever - Google Patents
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Abstract
The invention belongs to the technical field of African swine fever treatment, and particularly relates to a new application of a compound PLX51107 in preventing or treating African swine fever. The invention unexpectedly discovers that the compound PLX51107 can obviously inhibit the RNA and protein expression levels of p30 and p72 in ASFV, prevent viruses from invading host cells, and can be used for inhibiting the early infection of the ASFV; and the compound PLX51107 can remarkably increase the expression levels of genes such as TNF-alpha, NF-kappa B, IL-1 beta, IL-8 and the like after ASFV infection, up-regulate the transcription levels of TNF-alpha, NF-kappa B, IL-1 beta and IL-8 and enhance immune response; therefore, the compound PLX51107 can be used for preventing or treating African swine fever.
Description
Technical Field
The invention belongs to the technical field of African swine fever treatment, and particularly relates to a new application of a compound PLX51107 in preventing or treating African swine fever.
Background
African Swine Fever (ASF) is an acute virulent infectious disease characterized by Fever of pigs and organ bleeding of the whole body of pigs caused by African Swine Fever Virus (ASFV), and the death rate of domestic pigs is as high as 100%. The disease first outbreaks in kenya 1921 and then is widely prevalent in domestic and wild pigs throughout africa. The 20 th century was introduced into europe in the 50 s, and the disease was cured for 40 years throughout europe. However, the disease was again introduced into grurgia from eastern africa in 2007, and then widely disseminated in eastern europe and introduced into elocusk, the far east russia, 2017. At the beginning of 8 months in 2019, a Hurongrong researcher reports the epidemic situation of the African swine in the first instance of China, and the disease spreads to 30 provinces and municipalities in China within a short time of one year, so that the disease continues to threaten the pig industry, wherein compared with 8 months in 2018, the yield of the domestic pig in 9 months in 2019 is reduced by 40%, the price of pork is doubled since 8 months in 2019, the yield is reduced by more than 40% in China, and the loss is serious. As no effective vaccine or specific therapeutic medicine exists so far, once the epidemic situation of the African swine fever occurs, the epidemic situation can be controlled only by a killing means, but the mode not only causes economic loss, but also cannot meet the requirement of large-scale pig raising in China. Therefore, how to effectively control the ASF epidemic situation is one of the great challenges facing the pig industry in the world at present, and is also a major strategic subject to be urgently solved by ASF prevention and control in China.
The p30 and p72 are key structural proteins in ASFV, and can neutralize virus after the virus attacks susceptible cells, and inhibit the attachment, replication and internalization processes of the virus. Wherein p30 is the main structural protein constituting the virus particle, and is also an important surface antigen, and is closely related to host cell tropism, pathogenicity and immunogenicity; p30 is expressed early in ASF infection, usually produced 2-4h post infection, and is expressed continuously throughout the infection, involved in virus internalization, and is involved in virus invasion into host cells. And p72 is a capsid protein, is the main structural protein of the African swine fever virus, can protect the virus nucleic acid from being damaged by nuclease or other physicochemical factors in the environment, is involved in the infection process of the virus and has good immunogenicity, the protein is generated in the late stage of virus infection, p72 is an important antigen protein of ASFV, is the main component of virus icosahedron, is important for the formation of virus capsid, and is involved in virus binding cells.
Compound PLX51107 is a novel BET inhibitor. In vitro studies have shown that short-term (4 hour) PLX51107 treatment in cultured cells results in a dramatic down-regulation of c-Myc levels, but does not immediately elicit an apoptotic response. PLX51107 induced apoptosis after extended treatment times (16 hours or longer continuous culture). PLX51107 can cause accumulation of p21 and I κ B α, decrease cMYC levels, regulate expression of pro-and anti-apoptotic proteins. In vivo studies showed that PLX51107 was well tolerated in mice. In rodents and dogs, the half-life of PLX51107 was relatively short, less than 3 hours. PLX51107 has anti-tumor activity in preclinical animal models of chronic lymphocytic leukemia and aggressive lymphoma.
The invention unexpectedly discovers that the compound PLX51107 can obviously inhibit the RNA and protein expression levels of p30 and p72 in ASFV, prevent viruses from invading host cells, and can be used for inhibiting the early infection of the ASFV; and the compound PLX51107 can remarkably increase the expression levels of genes such as TNF-alpha, NF-kappa B, IL-1 beta, IL-8 and the like after ASFV infection, up-regulate the transcription levels of TNF-alpha, NF-kappa B, IL-1 beta and IL-8 and enhance immune response; therefore, the compound PLX51107 can be used for preventing or treating African swine fever.
Disclosure of Invention
In view of the above technical problems, the present invention aims to provide an application of a compound PLX51107 in the preparation of a drug for treating african swine fever, wherein the structural formula of the compound PLX51107 is shown as the following formula (i):
the invention also aims to provide an application of a compound PLX51107 in preparing a drug for preventing African swine fever, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of the compound PLX51107 in preparing a medicine for inhibiting transcription and expression of African swine fever virus genes, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of a compound PLX51107 in preparing a medicament for inhibiting the expression of African swine fever virus p30 RNA, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of a compound PLX51107 in preparing a medicament for inhibiting expression of P30 protein of African swine fever virus, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of a compound PLX51107 in preparing a medicament for inhibiting the expression of African swine fever virus p72 RNA, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of a compound PLX51107 in preparing a medicament for inhibiting expression of P72 protein of African swine fever virus, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
the invention also aims to provide an application of a compound PLX51107 in preparing a medicament for promoting the expression of an inflammatory factor, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
preferably, the inflammatory factors include TNF-alpha, NF-kappa B, IL-1 beta, IL-8.
Preferably, the compound PLX51107 is added with pharmaceutically acceptable carriers and/or excipients to be prepared into any one dosage form of tablets, sprays, granules, capsules, oral liquid, injections and suspensions.
The invention has the beneficial effects that: the invention unexpectedly discovers that the compound PLX51107 can obviously inhibit the RNA and protein expression levels of p30 and p72 in ASFV, prevent viruses from invading host cells, and can be used for inhibiting the early infection of the ASFV; and the compound PLX51107 can remarkably increase the expression levels of genes such as TNF-alpha, NF-kappa B, IL-1 beta, IL-8 and the like after ASFV infection, up-regulate the transcription levels of TNF-alpha, NF-kappa B, IL-1 beta and IL-8 and enhance immune response; therefore, the compound PLX51107 can be used for preventing or treating African swine fever.
Drawings
The compound PLX51107 of figure 1 inhibits the infection and replication of African swine fever virus;
FIG. 2 is a graph showing the results of the RNA expression levels of p30 and p 72;
FIG. 3 is a graph showing the results of the compound PLX51107 inhibiting the protein expression levels of African swine fever viruses p30 and p 72;
FIG. 4 is a graph showing the results of the compound PLX51107 up-regulating the expression of host inflammation-related factors;
figure 5 cytotoxicity results of compound PLX 51107.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments. The scope of the invention is not limited to the examples described below.
The experiments described in the following examples obtain biosafety permits and african swine fever laboratory activity permits:
according to the related requirements of biosafety of a Lanzhou veterinary research institute of the Chinese agricultural academy of sciences, a biological safety 3-level laboratory (BSL-3) and related biological safety of African swine fever, the Lanzhou veterinary research institute biological safety committee, the laboratory animal ethics committee, the Chinese agricultural academy of sciences biological safety committee, the Lanzhou veterinary research institute experimental animal ethics committee and the Lanzhou veterinary research institute biological safety committee report step by step, the permission of developing highly pathogenic ASFV pathogens and animal research is obtained by the agricultural department, and the permission is recorded by the agricultural rural department and meets the requirements of national biological safety level.
Experimental cells, viral sources as described in the examples below:
primary Porcine Alveolar Macrophages (PAM) and primary bone marrow macrophages (BMDM) were taken from healthy SPF Bama minipigs aged 2-4 months, aseptically collected, lysed with red blood cell lysate (purchased from Biosharp), red blood cells were removed, centrifuged at low speed, the supernatant was discarded, and the cell pellet was resuspended in RPMI 1640 complete medium (purchased from Gibco) containing 10% FBS (purchased from PAN), placed at 37 ℃ and 5% CO2Culturing in an incubator.
The ASFV gene II type strain (ASFV CN/SC/2019) is an African swine fever regional laboratory isolate of Lanzhou veterinary research institute of Chinese academy of agricultural sciences, and the virus titer is 5 multiplied by 107TCID50and/mL, which is the 4 th generation virus after PAM cell propagation, is subpackaged and stored in a foot and mouth disease reference laboratory (ABSL-3) of China and is reserved at the temperature of 80 ℃ below zero for later use.
PLX51107, available to seine autumn biosciences limited, brand: belleck, cat #: and S8739.
Other reagents in the experiment are common commercial reagents unless otherwise specified; the procedures in the experiments are those known in the art unless otherwise specified.
EXAMPLE 1 Effect of Compound PLX51107 on African Swine fever Virus infection replication and transcriptional expression of genes
1. Changes in African Swine fever Virus infection and replication
Culture of porcine alveolar macrophages (PAM, 2X 10) in RPMI 1640+ 10% FBS medium in 96-well plates5Per well), after the experimental group treated the cells with different concentrations of PLX51107 (0.5. mu.M, 1. mu.M, 2. mu.M, 5. mu.M, 8. mu.M, 10. mu.M) for 16h, the infection control group treated the cells with DMSO (1%) for 16 h; continuously diluting ASFV CN/SC/2019 strain (MOI is 0.1) by 10 times with PBS, making 8 dilutions, repeating 8 wells for each dilution, inoculating PAM cells for culture, and adding pig red cells; the cell plate was placed at 37 c,5％CO2conditioned for 3-6 days, and the erythrocyte adsorption reaction (HAD) in each cell culture well was observed daily.
The erythrocyte adsorption reaction (HAD) is based on the phenomenon that porcine red blood cells are adsorbed around mononuclear macrophages infected with african swine fever virus, thereby producing erythrocyte adsorption. The results are shown in FIG. 1, which infected HAD in control group (DMSO)50Higher value, and HAD after treatment with PLX51107 at different concentrations50The value decreased, wherein the HAD was found after treatment with PLX51107 at 8. mu.M50The value was reduced to half of the control (DMSO); when the dosage reaches 10 mu M, the phenomenon of red blood cell adsorption is basically avoided. The results show that the compound PLX51107 can obviously inhibit infection and replication of ASFV, and the inhibition effect is more obvious along with the increase of the concentration of the compound.
2. RNA transcript levels of p30 and p72
Porcine alveolar macrophages (PAM, 1X 10) were cultured in RPMI 1640+ 10% FBS medium in 48-well plates6Hole/bore); experimental groups cells were treated with different concentrations of PLX51107(0.5 μ M, 1 μ M, 2 μ M, 5 μ M, 8 μ M, 10 μ M) for 16h before infection with the ASFV CN/SC/2019 strain (MOI ═ 0.1); infection control group cells were treated with DMSO (1%) for 16h, followed by infection with ASFV CN/SC/2019 strain (MOI ═ 0.1); and (3) continuously culturing the cells infected with the ASFV CN/SC/2019 strain in the experimental group and the infected control group for 48h, collecting cell cultures, washing the cells once by PBS, centrifuging, and discarding the supernatant. Total RNA was extracted by Trizol method, cDNA was synthesized using the iScriptTM Reverse Transcription Supermix for RT-qPCR (Bio-Rad) kit, and the difference in expression of p30 and p72 RNAs was detected by Q-PCR.
The Q-PCR reaction system was 20. mu.L in total volume and contained 10. mu.M of upstream and downstream primers, 90ng of cDNA, 10. mu.L of SYBR Green supermix (2X) (Bio-Rad), and sterile deionized water to 20. mu.L. The reaction conditions are as follows: at 95 ℃ for 3 min; 95 ℃, 5s, 60 ℃, 30s, 40 cycles.
Wherein the sequence of the p30 primer is as follows: an upstream primer 5'-GAGGAGACGGAATCCTCAGC-3'; a downstream primer 5'-GCAAGCATATACAGCTTGGAGT-3';
the sequence of the p72 primer is as follows: an upstream primer 5'-CTGCTCATGGTATCAATCTTATCGA-3'; the downstream primer is 5 '-GATACCACAAGATCRGCCGT-3'.
The experimental results of the RNA expression levels of p30 and p72 are shown in figure 2, the compound PLX51107 can inhibit the RNA expression levels of p30 and p72 in the African swine fever virus gene, the inhibition rate of the compound PLX51107 dose of 1 mu M on the RNA expression level of p30 is higher than 50%, and the inhibition rate of the compound PLX51107 dose of 2 mu M on the RNA expression level of p72 reaches 50%.
3. protein expression levels of p30 and p72
Porcine alveolar macrophages (PAM, 10X 10) were cultured overnight in RPMI 1640+ 10% FBS medium in 35mm dishes6) (ii) a Experimental groups cells were treated with PLX51107(5 μ M) for 16h before infection with ASFV CN/SC/2019 strain (MOI ═ 0.1); uninfected controls treated cells with DMSO (1%) for 16 h; infection control group cells were treated with DMSO (1%) for 16h before infection with ASFV CN/SC/2019 strain (MOI ═ 0.1); after culturing the treated cells for another 48h, the cell culture was collected, the cells were washed once with PBS, centrifuged, and the supernatant was discarded. Extracting total protein, and detecting the expression difference of p30 and p72 proteins by using a western-blotting method.
p30 and p72 protein expression level test results as shown in FIG. 3, the expression levels of ASFV p30 and p72 proteins were increased in the infected control group (DMSO + ASFV) and the experimental group (PLX51107+ ASFV) compared to the uninfected control group (control group); however, the Ap30 and p72 protein expression levels in the experimental group (PLX51107+ ASFV) are significantly reduced relative to the infection control group (DMSO + ASFV). The result shows that the compound PLX51107 can obviously inhibit the expression levels of p30 and p72 proteins in the African swine fever virus gene.
The results show that the compound PLX51107 can obviously inhibit the RNA and protein expression levels of p30 and p72 in ASFV, prevent viruses from invading host cells, and can be used for inhibiting the early infection of ASFV.
EXAMPLE 2 Effect of Compound PLX51107 on the expression levels of factors associated with inflammation in hosts
Porcine alveolar macrophages (PAM, 1X 10) were cultured in RPMI 1640+ 10% FBS medium in 48-well plates6Hole/bore); experimental groups cells were treated with PLX51107(5 μ M) for 16h before infection with ASFV CN/SC/2019 strain (MOI ═ 0.1); the blank control group did not have anyProcessing; compound PLX51107 treatment group alone cells were treated with PLX51107(5 μ M) for 16h, without infection with ASFV CN/SC/2019 strain; virus-independent infection groups cells were treated with DMSO (1%) for 16h, followed by direct infection with ASFV CN/SC/2019 strain (MOI ═ 0.1); after the cells treated as above were cultured for another 48 hours, the cell culture was collected, the cells were washed once with PBS, centrifuged, and the supernatant was discarded. After total RNA was extracted and cDNA was reverse transcribed, differences in expression of host inflammation-associated factors were detected by Q-PCR (as described above).
Wherein the TNF-alpha primer sequence is as follows: an upstream primer 5'-GGCTGCCTTGGTTCAGATGT-3'; a downstream primer 5'-CAGGTGGGAGCAACCTACAGTT-3';
the NF-kappa B primer sequence is as follows: an upstream primer 5'-TCCAACACCGCATAAACC-3'; a downstream primer 5'-TAAAGCTCACCCGCAACG-3';
the IL-1 beta primer sequence is as follows: an upstream primer 5'-AGGGACATGGAGAAGCGATTT-3'; a downstream primer 5'-TTCTGCTTGAGAGGTGCTGATG-3';
the IL-8 primer sequence is: an upstream primer 5'-TTCCTGCTTTCTGCAGCTCTCT-3'; the downstream primer 5'-GGGTGGAAAGGGTGTGGAATG-3'.
The experimental results are shown in fig. 4, compared with the blank Control group (Control), the expression levels of TNF- α and NF- κ B genes in the compound I-BET-762 single-treated group (PLX51107 alone) are significantly reduced, and the expression levels of TNF- α and NF- κ B genes in the virus single-infected group (DMSO + ASFV) and the experimental group (PLX51107+ ASFV) are increased, wherein the expression levels of TNF- α and NF- κ B genes in the experimental group (PLX51107+ ASFV) are significantly increased compared with the virus single-infected group (DMSO + ASFV); compared with a blank Control group (Control), the IL-1 beta and IL-8 gene expression levels in the compound PLX51107 single-treatment group (PLX51107 alone), the virus single-infection group (DMSO + ASFV) and the experimental group (PLX51107+ ASFV) are increased, wherein the gene expression levels of TNF-alpha, NF-kappa B, IL-1 beta, IL-8 and the like in the experimental group (PLX51107+ ASFV) are remarkably increased compared with the compound PLX51107 single-treatment group (PLX51107 alone) and the virus single-infection group (DMSO + ASFV). The result shows that the compound PLX51107 can remarkably up-regulate the expression levels of genes such as TNF-alpha, NF-kappa B, IL-1 beta, IL-8 and the like after ASFV virus infection, up-regulate the transcription levels of TNF-alpha, NF-kappa B, IL-1 beta and IL-8, enhance immune response and can be used for preventing or treating African swine fever.
EXAMPLE 3 cytotoxicity of Compound PLX51107
The cytotoxicity detection is carried out on the small molecular compound PLX51107 by a CCK-8 method by utilizing the constructed stable in-vitro cell screening system. Culture of porcine alveolar macrophages (PAM, 2X 10) in RPMI 1640+ 10% FBS medium in 96-well plates5Per well), overnight incubation, adding different concentrations of PLX51107 (0.5. mu.M, 1. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 40. mu.M, 80. mu.M, 160. mu.M, 240. mu.M) to wells with blank wells (containing medium only), control wells (containing cells and medium), after incubating the plates in the incubator for 16h, adding 10. mu.L of CCK-8 solution to each well of the plate, incubating the plates in the incubator for 1-4h, and gently mixing on a shaker before reading the plates. And reading the absorbance at 450nm by a microplate reader, and calculating the cell survival rate.
The results are shown in fig. 5, the compound PLX51107 has low toxicity to cells, even when the dosage reaches 80 μ M, the cell activity still reaches more than 50%, the cytotoxicity is low, and the safety is good.
In conclusion, the compound PLX51107 provided by the invention has a good inhibition effect on African swine fever viruses, can enhance immune response, has low cytotoxicity and good safety, and can be used for preventing or treating African swine fever viruses.
The above embodiments are merely preferred embodiments of the present invention, and not intended to limit the scope of the invention, so that equivalent changes or modifications made based on the structure, characteristics and principles of the invention should be included in the claims of the present invention.
Claims (8)
1. The application of a compound PLX51107 in preparing a medicament for treating African swine fever is disclosed, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
（Ⅰ）。
2. the application of a compound PLX51107 in preparing a drug for preventing African swine fever is disclosed, wherein the structural formula of the compound PLX51107 is shown as the following formula (I):
（Ⅰ）。
3. the use according to claim 1 or 2, wherein the compound PLX51107 achieves the treatment or prevention of african swine fever virus by inhibiting the expression of p30 RNA.
4. The use of claim 1 or 2, wherein the compound PLX51107 achieves the treatment or prevention of african swine fever by inhibiting the expression of the p30 protein.
5. The use according to claim 1 or 2, wherein the compound PLX51107 achieves the treatment or prevention of african swine fever virus by inhibiting the expression of p72 RNA.
6. The use of claim 1 or 2, wherein the compound PLX51107 achieves the treatment or prevention of african swine fever by inhibiting the expression of the p72 protein.
7. The use of claim 1 or 2, wherein the compound PLX51107 is for the treatment or prevention of african swine fever by promoting the expression of inflammatory factors, including TNF- α, NF- κ B, IL-1 β, IL-8.
8. The use of claim 1 or 2, wherein the compound PLX51107 is formulated into any one of tablets, sprays, granules, capsules, oral liquids, and injections, with the addition of pharmaceutically acceptable carriers and/or excipients.
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| CN110012667A (en) * | 2016-09-02 | 2019-07-12 | 葛兰素史克知识产权开发有限公司 | Compound (2S, 3R) -2- (((2- (1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- base) -1- ((tetrahydro -2H- pyrans -4- base) methyl) -1H- benzo [d] imidazoles -5- base) methyl) amino) -3-hydroxybutyrate isopropyl ester ethanedisulphonate crystalline hydrate |
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| CN109790147A (en) * | 2016-09-02 | 2019-05-21 | 葛兰素史克知识产权第二有限公司 | Imdazole derivatives and its purposes in treatment autoimmunity or inflammatory disease or cancer |
| CN110012667A (en) * | 2016-09-02 | 2019-07-12 | 葛兰素史克知识产权开发有限公司 | Compound (2S, 3R) -2- (((2- (1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- base) -1- ((tetrahydro -2H- pyrans -4- base) methyl) -1H- benzo [d] imidazoles -5- base) methyl) amino) -3-hydroxybutyrate isopropyl ester ethanedisulphonate crystalline hydrate |
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