CN113082049B - New application of potassium iodide or composition containing potassium iodide in preparation of drugs for treating African swine fever - Google Patents
New application of potassium iodide or composition containing potassium iodide in preparation of drugs for treating African swine fever Download PDFInfo
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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 potassium iodide or a composition containing potassium iodide in preventing or treating African swine fever. The invention unexpectedly discovers that potassium iodide (KI) can inhibit the expression of African swine fever virus proteins p72 and p30, inhibit the gene copy number and virus titer of the African swine fever virus, inhibit the replication and infection of ASFV, and is used for preventing or treating African swine fever; meanwhile, the invention discovers that potassium iodide (KI) combined with ML-60218 can obviously inhibit the expression of African swine fever virus proteins p30 and p72, prevent viruses from invading host cells and can be used for inhibiting the whole period of ASFV infection; in addition, potassium iodide (KI) combined with ML-60218 can obviously inhibit the replication of African swine fever virus and reduce the virus titer after the African swine fever virus infection, and can be used as an inhibitor of the African swine fever virus for preventing or treating the African swine fever virus.
Description
Technical Field
The invention belongs to the technical field of African swine fever treatment, and particularly relates to a new application of potassium iodide or a composition containing potassium iodide 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. In 2019, at the beginning of 8 months, researchers of Hurongrong report the epidemic situation of the first African swine fever in 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. 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.
p30 and p72 are key structural proteins in ASFV, are main structural proteins constituting virus particles, are also important surface antigens, and are 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; p72 is expressed in the late stage of ASF infection, usually beginning at about 9h after infection, and then continuing to express, and it exists mainly in the form of trimer on the surface of African swine fever virus capsid, and is a more typical 'double jelly roll' structure.
Potassium iodide (KI), an inorganic compound, is used as a raw material for the manufacture of organic compounds and pharmaceuticals. Iodide has a good biological effect: both fluoride and iodide kill the bacteria streptococci that cause dental bacteria, and the topical application of potassium iodide is not valuable for treating ginitis and otitis media; compared with seaweed, potassium iodide has greater anti-infection ability and is more popular in treating ulcer, cyst and skin infection.
ML-60218, 2-chloro-N- [3- (5-chloro-3-methylbenzo [ b ] thiophen-2-yl) -1-methyl-1H-pyrazol-5-yl ] -benzenesulfonamide, is a small molecule inhibitor of Saccharomyces cerevisiae and human RNA polymerase III. At 200. mu.M, there was 88%, 94% and 90% inhibition of the in vitro transcription activity of Saccharomyces cerevisiae, Candida albicans and human RNA polymerase III, respectively. Among them the literature (Melchjorsen J, et al. early Innate Recognition of drugs Simplex Virus in Human Primary Phages Is meditated via the MDA 5/MAVS-dependents and MDA 5/MAVS/RNAPOSOMerase III-indendependent Pathways.) discloses that RNA polymerase III inhibitor ML60218 does not inhibit the interferon IFN-. beta.and TNF-. alpha.levels after HSV-1 infection, i.e. ML60218 does not inhibit the replication of HSV-1 Virus.
The invention unexpectedly discovers that potassium iodide (KI) can inhibit the expression of African swine fever virus proteins p72 and p30, inhibit the gene copy number and virus titer of the African swine fever virus, inhibit the replication and infection of ASFV, and is used for preventing or treating African swine fever; meanwhile, potassium iodide (KI) is combined with ML-60218, so that the expression of African swine fever virus proteins p30 and p72 can be obviously inhibited, the virus is prevented from invading host cells, and the combined virus inhibitor can be used for inhibiting the whole period of ASFV infection; the inhibitor can obviously inhibit the replication of the African swine fever virus, reduce the virus titer after the African swine fever virus infection, can be used as an inhibitor of the African swine fever virus for preventing or treating the African swine fever virus, and has obviously better effect than that of singly using potassium iodide and ML-60218.
Disclosure of Invention
In view of the above technical problems, the present invention aims to provide a novel use of potassium iodide or a composition containing potassium iodide for inhibiting african swine fever virus. The method specifically comprises the following scheme:
in a first aspect, the invention provides an application of potassium iodide in preparation of a drug for treating African swine fever.
Preferably, the potassium iodide is added with a pharmaceutically acceptable carrier and/or an auxiliary material to prepare any one of tablets, sprays, granules, capsules, oral liquid, injections and suspensions.
In a second aspect, the invention provides an application of potassium iodide in preparing a drug for preventing African swine fever.
Preferably, the potassium iodide is added with a pharmaceutically acceptable carrier and/or an auxiliary material to prepare any one of tablets, sprays, granules, capsules, oral liquid, injections and suspensions.
In a third aspect, the present invention provides a pharmaceutical composition for preventing or treating African swine fever, comprising potassium iodide and a compound ML-60218 or a pharmaceutically acceptable salt thereof, wherein the compound ML-60218 has a structural formula shown in formula (I),
preferably, the molar ratio of the potassium iodide to the compound ML-60218 or a pharmaceutically acceptable salt thereof is 6.25-400. mu.M: 3.125-200. mu.M.
Preferably, the molar ratio of the potassium iodide to the compound ML-60218 or a pharmaceutically acceptable salt thereof is 6.25-200. mu.M: 3.125-100. mu.M.
Preferably, the molar ratio of potassium iodide to compound ML-60218 or a pharmaceutically acceptable salt thereof is 100 μ M to 50 μ M.
In a fourth aspect, the invention provides an application of the pharmaceutical composition of the third aspect in preparing a drug for preventing African swine fever.
In a fifth aspect, the invention provides an application of the pharmaceutical composition of the third aspect in preparing a drug for preventing African swine fever.
Preferably, the pharmaceutical composition of the third aspect is added with a pharmaceutically acceptable carrier and/or adjuvant, and made into any dosage form of tablets, sprays, granules, capsules, oral liquids, and injections.
The invention has the beneficial effects that: the invention unexpectedly discovers that potassium iodide (KI) can inhibit the expression of African swine fever virus proteins p72 and p30, inhibit the gene copy number and virus titer of the African swine fever virus, inhibit the replication and infection of ASFV, and is used for preventing or treating African swine fever; meanwhile, potassium iodide (KI) is combined with ML-60218, so that the expression of African swine fever virus proteins p30 and p72 can be obviously inhibited, the virus is prevented from invading host cells, and the combined virus inhibitor can be used for inhibiting the whole period of ASFV infection; the inhibitor can obviously inhibit the replication of the African swine fever virus, reduce the virus titer after the African swine fever virus infection, can be used as an inhibitor of the African swine fever virus for preventing or treating the African swine fever virus, and has obviously better effect than that of singly using potassium iodide and ML-60218.
Drawings
FIG. 1 Virus titre following African swine fever virus infection;
FIG. 2 African swine fever virus infection gene copy number;
FIG. 3 is a graph showing the results of the expression levels of p30 and p72 proteins;
FIG. 4 is a graph of the cytotoxicity results of potassium iodide in combination with ML-60218.
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 CN/GS/2018 isolate comes from the national African swine fever regional laboratory (Lanzhou), belongs to genotype II, and has the virus titer of 5 multiplied by 107TCID50The strain/mL is the 4 th generation strain after PAM cell propagation, is preserved in China center for type culture Collection in 12 months and 21 days in 2020, and has the preservation number of CCTCC NO: v202096; and (4) storage address: wuhan, Wuhan university, China; and (4) contacting the telephone: 027-68752319.
Potassium iodide (KI), purchased from Solarbio corporation.
ML-60218(C19H15Cl2N3O2S2) Purchased from MedChemExpress corporation.
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 KI and ML-60218 on replication of African Swine fever Virus infection and Gene transcription expression
1. Changes in African Swine fever Virus infection and replication
Culture of porcine alveolar macrophages (PAM, 1X 10) in 12-well plates with RPMI 1640+ 10% FBS medium6Perwell), the experimental groups were infected with ASFV CN/GS/2018 strain (0.1MOI)24h after 2h treatment with KI (100. mu.M), ML-60218 (50. mu.M), KI (100. mu.M) and ML-60218 (50. mu.M) compositions, respectively; the empty cells and the empty cells were inoculated with ASFV CN/GS/2018 strain (0.1MOI) for 24h as a control. Collecting differently processed cells and supernatant, repeatedly freezing and thawing at-80 deg.C for 3 times, diluting with serum-free RPMI 1640 for 10 times, making 7 dilutions, repeating 8 holes for each dilution, inoculating to PAM cell, culturing, and adding pig red blood cell; place the cell plate at 37 ℃ in 5% CO2The cells were cultured under the conditions for 5 days, and the erythrocyte adsorption reaction (HAD) in each cell culture well was observed every day. Calculation of HAD50, the calculation method of which refers to TCID50The method of (3).
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 of the experiments are shown in FIG. 1, HAD in the Single-virus group (Control group)50Has high value, and HAD is processed with KI and ML-6021850The value is reduced, and the KI is combined with the HAD after the ML-60218 processing50The value decreases significantly. The results show that KI combined with ML-60218 can obviously inhibit the virus titer of ASFV.
2. Copy number of gene
Culture of porcine alveolar macrophages (PAM, 1X 10) in 12-well plates with RPMI 1640+ 10% FBS medium6Perwell), the experimental groups were infected with ASFV CN/GS/2018 strain (0.1MOI)24h after 2h treatment with a composition of KI (100. mu.M), ML-60218 (50. mu.M), KI (100. mu.M) and ML-60218 (50. mu.M), respectively; the empty cells and the empty cells were inoculated with ASFV CN/GS/2018 strain (0.1MOI) for 24h as a control. Collecting cells and supernatant after different treatments, and repeatedly freezing and thawing at-80 deg.C for 3 times to obtain samples. The Ct values of different processed samples are directly detected by using a Pro Taq HS premixed probe method qPCR kit (ACCURATE BIOLOGY), and the change of the gene copy number is obtained according to a standard curve.
The total volume of the Q-PCR reaction system is 25 mu L, and the Q-PCR reaction system comprises: 12.5 mu L of 2x pro taq HS probe premix, 2.5 mu L of upstream and downstream primers, 1 mu L of probe and 2.5 mu L of inactivated venom are used as templates, and sterile deionized water is supplemented to 25 mu L;
the reaction conditions are as follows: at 95 ℃ for 2 min; at 95 ℃ for 7 s; at 60 ℃ for 12 s; 3 cycles; 95 ℃ for 6 s; at 58 ℃ for 11 s; 40 cycles;
a forward primer 5'-GATACCACAAGATCAGCCGT-3'; a reverse primer 5'-CTGCTCATGGTATCAATC TTATCGA-3'; probe FAM-CCACGGGAGGAATACCAACCCAGTG-TAMRA.
The gene copy number detection results are shown in FIG. 2, the gene copy number of ASFV in the KI and ML-60218 single-treatment group is lower than that of the single-virus group (Control group), and the gene copy number of ASFV in the KI combined ML-60218 treatment group is significantly lower than that of the single-virus group (Control group), which indicates that the KI combined ML-60218 can significantly inhibit the expression and replication of African swine fever virus.
P30, p72 protein expression level
Porcine alveolar macrophages (PAM, 10X 10) were cultured overnight in 12-well plates in RPMI 1640+ 10% FBS medium6) (ii) a The experimental group was infected with ASFV CN/GS/2018 strain (0.1MOI) after being treated with a composition of KI (100. mu.M), ML-60218 (50. mu.M), KI (100. mu.M) and ML-60218 (50. mu.M), respectively, for 2 h; the empty cells and the empty cells were inoculated with ASFV CN/GS/2018 strain (0.1MOI) as a control, and after 24 hours, 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 a western-blotting method.
The experimental results of the p30 and p72 protein expression levels are shown in FIG. 3, and compared with the uninfected Control group (Mock group), the ASFV p30 and p72 proteins are expressed in the infected Control group (Control group) and the experimental group (KI group, ML-60218 group and KI + ML-60218 group); but the expression levels of ASFV p30 and p72 proteins were reduced in the KI group and ML-60218 group relative to the infection Control group (Control group); and the expression level of ASFV p30 and p72 proteins in the KI + ML-60218 group is obviously reduced. The results show that the KI combined with the ML-60218 can obviously inhibit the protein expression levels of p30 and p72 in the African swine fever virus gene, prevent the virus from invading host cells, and can be used for inhibiting the whole cycle of ASFV infection.
Example 2 cytotoxicity of KI in combination with ML-60218
And (3) carrying out cytotoxicity detection on the small molecular compound KI combined with ML-60218 by using the constructed stable in-vitro cell screening system and a CCK-8 method. 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 KI (6.25. mu.M, 12.5. mu.M, 25. mu.M, 50. mu.M, 100. mu.M, 200. mu.M, 400. mu.M) and ML-60218 (3.125. mu.M, 6.25. mu.M, 12.5. mu.M, 25. mu.M, 50. mu.M, 100. mu.M, 200. mu.M) to the wells, while setting blank wells (containing medium only), control wells (containing cells and medium), after incubating the plates in the incubator for 2h, adding 10. mu.L of CCK-8 solution to each well of the plate, incubating the plates in the incubator for 1-4h, and mixing gently on a shaker before reading the plates. And reading the absorbance at 450nm by a microplate reader, and calculating the cell survival rate.
As shown in FIG. 4, the results show that 6.25-400 μ M KI combined with 3.125-200 μ M ML-60218 has a low effect on cell viability, and that 6.25-200 μ M KI combined with 3.125-100 μ M ML-60218 has little toxicity to cells and is highly safe.
In conclusion, the KI and the KI combined with the ML-60218 can obviously inhibit the expression of African swine fever virus proteins p30 and p72, prevent viruses from invading host cells, and can be used for inhibiting the whole cycle of ASFV infection; and the KI combined with the ML-60218 can obviously inhibit the replication of the African swine fever virus, reduce the virus titer after the African swine fever virus infection, and can be used as an inhibitor of the African swine fever virus for preventing or treating the African swine fever.
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 (7)
1. Application of potassium iodide in preparing medicine for treating African swine fever is provided.
2. The use of claim 1, wherein the potassium iodide is added with pharmaceutically acceptable carriers and/or excipients to prepare any one of tablets, sprays, granules, capsules, oral liquids and injections.
3. A pharmaceutical composition for the treatment of african swine fever comprising potassium iodide and compound ML-60218 or a pharmaceutically acceptable salt thereof; the structural formula of the compound ML-60218 is shown as the following formula (I),
4. the pharmaceutical composition of claim 3, wherein the molar ratio of potassium iodide to compound ML-60218 or a pharmaceutically acceptable salt thereof is 6.25-400 μ M to 3.125-200 μ M.
5. The pharmaceutical composition of claim 4, wherein the molar ratio of potassium iodide to compound ML-60218 or a pharmaceutically acceptable salt thereof is 100 μ M to 50 μ M.
6. Use of a pharmaceutical composition according to any one of claims 3 to 5 in the manufacture of a medicament for the treatment of African swine fever.
7. The pharmaceutical composition of any one of claims 3-5, in combination with a pharmaceutically acceptable carrier and/or adjuvant, is formulated into any one of the dosage forms of tablet, spray, granule, capsule, oral liquid, and injection.
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| CN114469913B (en) * | 2022-02-17 | 2024-03-22 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Use of Tilorone for preventing/treating African swine fever virus infection |
| CN115192599B (en) * | 2022-08-11 | 2024-01-16 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Application of gamithromycin in preparation of preparation for treating African swine fever |
| CN115252625B (en) * | 2022-08-11 | 2024-01-26 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Application of cyclovirobuxine D in preparation of preparation for treating African swine fever |
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