CN115813914B - Application of compound KYP-2047 in preparation of antiviral drugs - Google Patents
Application of compound KYP-2047 in preparation of antiviral drugs Download PDFInfo
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Abstract
The invention belongs to the technical field of biology, and particularly relates to application of a compound KYP-2047 in preparation of antiviral drugs. The invention surprisingly discovers that the compound KYP-2047 can reduce the replication level of foot-and-mouth disease viruses and the Seika viruses, inhibit the expression of structural proteins of the foot-and-mouth disease viruses and the Seika viruses, has the effect of inhibiting the infection of the foot-and-mouth disease viruses and the Seika viruses, can be used for preparing medicines or adjuvants for resisting the infection of the foot-and-mouth disease viruses and the Seika viruses, and is used for inhibiting the replication of the foot-and-mouth disease viruses and the Seika viruses. However, the invention is not limited to foot-and-mouth disease virus and sai-card virus, and on the basis that the compounds KYP-2047 can inhibit the replication of foot-and-mouth disease virus and sai-card virus, the compounds can also inhibit the replication of other viruses of the picornaviridae family, and can also be used for inhibiting the replication of other viruses to prepare medicaments or adjuvants for resisting viral infection.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of a compound KYP-2047 in preparation of antiviral drugs.
Background
Foot and mouth disease virus (Foot and mouth disease virus, FMDV) belongs to Picornaviridae (Picornaviridae) and Aphthovirus (Aphthovirus), the genome is single-strand positive strand RNA, about 8500nt, FMDV mainly infects artiodactyls such as pigs, cows and sheep to cause acute, febrile, highly contagious and rapidly and remotely transmissible animal virulent infectious diseases, and more than 70 susceptible animals; causes the skin or hairless parts of the mouth mucosa, hooves, breasts and the like to have the symptoms of blisters and ulcers, and leads to the reduction or loss of productivity. The disease can cause huge economic loss and social political influence of animal husbandry, is an animal epidemic disease which is listed as legal report by the world animal health organization (WOAH), and is also a class I animal epidemic disease which is important to prevent in China. To date, FMDV has remained popular in various countries and regions, comprising strains of 7 serotypes (A, O, C, SAT, SAT2, SAT3 and Asia 1), more than 80 subtypes, without effective cross protection between the different serotypes, which makes control of FMD more difficult. Currently, vaccination is the most effective measure against FMD. However, research on host immunity, pathogenesis and the like caused by pathogenic variation is still to be broken through. Therefore, the method is of great importance to screening and research of drugs for inhibiting foot-and-mouth disease virus infection.
Senecavirus A (SVA) belongs to Picornaviridae, members of Senecavirus, and is one of the causative agents of swine vesicular disease. The first SVA strain, SVV-001, was isolated from conventional cell culture in 2002. SVA comprises a single-stranded positive sense RNA genome that encodes a polypeptide that is cleaved into leader protein L and three precursor proteins P1, P2, and P3. Subsequently, P1 is cleaved into VP4, VP2, VP3 and VP1 structural proteins, while P2 and P3 are cleaved into 2A, 2B, 2C, 3A, 3B, 3C and 3D nonstructural proteins. SVA can cause vesicular damage, somnolence, anorexia, lameness, and even acute death of piglets to the oral and nasal mucosa of the pig. Since SVA induces vesicular disease similar to FMDV, porcine vesicular disease virus (SVDV) and Vesicular Stomatitis Virus (VSV), it is clinically difficult to distinguish.
Compounds KYP-2047 were originally synthesized as one of the derivatives of prolyl oligopeptidase inhibitor JTP-4819 and had better pharmacological properties (i.e. higher brain penetration, even distribution in hippocampus, striatum and cortex, better availability at intracellular sites).
The invention surprisingly discovers that the compound KYP-2047 can reduce the replication level of FMDV and SVA, inhibit the expression of virus structural proteins, has the effect of inhibiting virus infection, and can be used for preparing medicines or adjuvants for resisting picornavirus infection and inhibiting the replication of viruses.
Disclosure of Invention
The invention provides application of a compound KYP-2047 in preparation of an antiviral infection medicine. The method specifically comprises the following steps:
in a first aspect, the invention provides an application of a compound KYP-2047 or pharmaceutically acceptable salt thereof in preparing a medicament for preventing virus infection, wherein the structural formula of the compound KYP-2047 is shown as the following formula (I):
preferably, the virus is a picornaviridae virus.
Preferably, the virus is a foot-and-mouth disease virus, a sai card virus.
Preferably, the compound KYP-2047 or pharmaceutically acceptable salt thereof is added with pharmaceutically acceptable carriers and/or auxiliary materials to prepare any pharmaceutically acceptable dosage form.
Preferably, the dosage forms comprise powder injection, capsules, tablets and suspensions.
In a second aspect, the invention provides application of a compound KYP-2047 or pharmaceutically acceptable salt thereof in preparing a medicament for treating viral infection, wherein the structural formula of the compound KYP-2047 is shown in the following formula (I):
preferably, the virus is a picornaviridae virus.
Preferably, the virus is a foot-and-mouth disease virus, a sai card virus.
Preferably, the compound KYP-2047 or pharmaceutically acceptable salt thereof is added with pharmaceutically acceptable carriers and/or auxiliary materials to prepare any pharmaceutically acceptable dosage form.
Preferably, the dosage forms comprise powder injection, capsules, tablets and suspensions.
The beneficial effects of the invention are as follows: the invention surprisingly discovers that the compound KYP-2047 can reduce the replication level of FMDV and SVA, inhibit the expression of virus structural proteins, has the effect of inhibiting virus infection, and can be used for preparing medicines or adjuvants for resisting picornavirus infection and inhibiting the replication of viruses.
Drawings
Results of the effect of compounds KYP-2047 of fig. 1 on FMDV titers;
FIG. 2 is a graph of the results of compounds KYP-2047 inhibiting FMDV replication in IBRS-2 cells;
FIG. 3 is a graph showing the results of compounds KYP-2047 inhibiting the expression of FMDV structural protein VP 1;
FIG. 4 results of the effect of compounds KYP-2047 on SVA titer;
FIG. 5 is a graph showing the results of compounds KYP-2047 inhibiting SVA replication in IBRS-2 cells;
FIG. 6 is a graph showing the results of compounds KYP-2047 inhibiting expression of SVA structural protein VP 2;
safety of compounds KYP-2047 of FIG. 7.
Detailed Description
The invention is further described in connection with the following detailed description, in order to make the technical means, the creation characteristics, the achievement of the purpose and the effect of the invention easy to understand. The scope of the invention is not limited to the examples described below.
The experiments described in the examples below obtained biosafety permissions and foot and mouth disease laboratory activity permissions:
the national institute of agricultural science, the biological safety committee of the national institute of veterinary science, the laboratory animal ethics committee of the national institutes of agricultural science, the biological safety committee of the national institutes of agricultural science, the laboratory animal ethics committee of the national institute of veterinary science, the biological safety committee of the national institute of veterinary science, the method obtains the research permission of the agricultural department on developing pathogens such as FMDV and animals, and has been recorded in the agricultural rural department, thereby meeting the requirements of the national biosafety level.
Experimental cells, viral sources as described in the examples below:
cell culture: IBRS-2 cells were derived from animals of the porcine family (Sus-scrofa), and BHK-21 cells were stored in the laboratory; the culture medium containing 10% Fetal Bovine Serum (FBS) and 1% diabody was placed in DMEM medium containing 5% CO 2 Culturing was performed in an incubator (37 ℃).
Viral origin: FMDV strains (O/BY/CHA/2010) and SVA strains (CH/FJ/2017) were saved in the national institute of veterinary science, department of agriculture, academy of china, foot-and-mouth disease and new disease epidemiology team and national foot-and-mouth disease reference laboratory.
Compounds KYP-2047 are available from MCE company under the accession numberHY-100475；
The experimental methods in the following examples are all conventional methods unless otherwise specified; the test materials used in the examples described below, unless otherwise specified, were purchased from conventional Biochemical reagent companies.
Example 1 Compounds KYP-2047 inhibit replication of FMDV
1. Preparation of Medium containing Compounds KYP-2047
KYP-2047 dry powder is dissolved in DMSO to prepare a stock solution with the concentration of 10 mM. Before the experiment, different doses of compounds KYP-2047 were added to the DMEM medium to give concentrations of 1.0. Mu.M, 10. Mu.M and 100. Mu.M, respectively.
2. Sample preparation of cells incubated with Compounds KYP-2047
IBRS-2 cells were counted and plated in six well plates, after treatment of cells with KYP-2047 (1 μm, 10 μm and 100 μm) at different concentrations for 4h in the experimental group and DMSO (1%) in the control group for 4h after cell growth to 70% -80% confluence; FMDV (moi=0.1) was then inoculated, the inoculation liquid was discarded 1h after inoculation, the cells were washed once with PBS, the maintenance liquid was supplemented, and the supernatant and cells were harvested 12-14 h after inoculation, respectively. Taking unvaccinated FMDV strain as a Mock control; DMSO (without compounds KYP-2047) was used as a blank.
Fmdv titer assay
Determining TCID of the supernatant obtained in the above step 2 50 Virus titer analysis was performed.
TCID 50 The measurement steps of (a) are as follows: BHK-21 cells were seeded into 96-well plates 16h in advance, after cells formed into monolayers, IBRS-2 cells were washed 3 times with PBS, and the supernatant collected in step 2 was seeded (10 -1 ～10 -10 Multiple dilution) was used as an infection well, and two additional rows of negative control wells were provided. 100 mu L of virus filtrate or dilution of the virus dilution with a multiple ratio is added into the infection hole, and the virus is adsorbed for 1h at 37 ℃ and is gently shaken every 10min, so that the virus adsorption is ensured to be uniform. After 1h of adsorption, the supernatant was aspirated and the plate was gently washed 1 time with PBS. Adding virus maintenance solution, observing cytopathic effect every 12h after 48h, recording pathological hole number after 72h, and calculating TCID 50 Three replicates were assayed and the average was taken as the final viral titer.
The experimental results are shown in FIG. 1, in which IBRS-2 cells were treated with compounds KYP-2047 during the culture, and the TCID of FMDV was obtained 50 Significantly reduced and dose dependent. It is shown that compounds KYP-2047 significantly reduce the viral titer of FMDV, inhibiting replication of FMDV.
Determination of FMDV replication
The viral RNA copy number in the supernatant obtained in step 2 above was measured, and viral RNA replication analysis was performed.
The viral RNA replication assay steps are as follows: viral RNA in the harvested samples was extracted according to the instructions of the viral RNA extraction kit (OMEGA Co.) and fluorescent quantitative PCR amplification was performed using the one-step qPCR kit (TAKARA Co.) to detect the copy number of the RNA-dependent RNA replicase 3D gene of FMDV.
qPCR reaction system: the total volume was 20. Mu.L, including 10. Mu.M of each of the upstream and downstream primers and the fluorescent-labeled probe, 0.4. Mu.L, 10. Mu.L of 2 XOne Step RT-PCR Buffer III, 0.4. Mu.L of TaKaRa Ex Taq HS (5U/. Mu.L), 0.4. Mu.L of PrimeScript RT Enzyme Mix II, 90ng of RNA 2. Mu.L, and 5.6. Mu.L of RNase Free dH 2O. The reaction conditions are as follows: 42 ℃, 5min,95 ℃, 10s,1cycle;95 ℃, 5s,60 ℃, 20s,40cycles.
Wherein the primer and probe sequences of qPCR are: upstream primer 5'-ACTGGGTTTTACAAACCTGTGA-3', downstream primer 5'-GCGAGTCCTGCCACGGA-3', fluorescent labeled probe 5'-FAM-TCCTTTGCACGCCGTGGGAC-TAMRA-3'.
The results are shown in FIG. 2, where RNA replication of FMDV was significantly reduced and dose dependent upon addition of compounds KYP-2047 during IBRS-2 cell culture. Compounds KYP-2047 were shown to significantly inhibit RNA replication of FMDV. Expression of FMDV structural protein VP1
And (3) measuring the expression of the FMDV structural protein VP1 in the cell sample, and carrying out virus structural protein expression level analysis.
The viral structural protein expression level analysis steps are as follows: IBRS-2 cells were counted and plated in 35mm dishes, after treatment of the experimental group with KYP-2047 (1 μm, 10 μm and 100 μm) at different concentrations for 4h and after treatment of the control group with DMSO (1%) for 4h when the cells were grown to 80% confluency; then, FMDV (MOI=0.1) was inoculated, the inoculated liquid was discarded 1h after inoculation, the cells were washed once with PBS, the maintenance liquid was supplemented, and the cells were harvested 12-14 h after inoculation, respectively. Taking unvaccinated FMDV strain as a Mock control; DMSO (without compounds KYP-2047) was used as a blank. Extracting total protein, and carrying out Western-blotting experiment to detect the expression difference of FMDV VP1 protein.
As a result, as shown in FIG. 3, the expression of FMDV structural protein VP1 was significantly reduced and dose-dependent after the addition of compounds KYP-2047 during the cultivation of IBRS-2 cells. The compound KYP-2047 obviously inhibits the expression of FMDV structural protein VP1 and inhibits the replication and infection of FMDV.
EXAMPLE 2 Compounds KYP-2047 inhibit SVA replication
1. Preparation of Medium containing Compounds KYP-2047
KYP-2047 dry powder is dissolved in DMSO to prepare a stock solution with the concentration of 10 mM. Before the experiment, different doses of compounds KYP-2047 were added to the DMEM medium to give concentrations of 1.0. Mu.M, 10. Mu.M and 100. Mu.M, respectively.
2. Sample preparation of cells incubated with Compounds KYP-2047
IBRS-2 cells were counted and plated in six well plates, after treatment of cells with KYP-2047 (1 μm, 10 μm and 100 μm) at different concentrations for 4h in the experimental group and DMSO (1%) in the control group for 4h after cell growth to 70% -80% confluence; SVA (MOI=0.1) was then inoculated, the inoculation liquid was discarded 1h after inoculation, the cells were washed once with PBS, the maintenance liquid was supplemented, and the supernatant and the cells were harvested 12-14 h after inoculation, respectively. Taking a non-inoculated SVA strain as a Mock control; DMSO (without compounds KYP-2047) was used as a blank.
SVA titre assay
Determining TCID of the supernatant obtained in the above step 2 50 Virus titer analysis was performed.
TCID 50 The measurement steps of (a) are as follows: IBRS-2 cells were seeded 16h in advance in 96-well plates, after cell formation into monolayer cells, the cells were washed 3 times with PBS, and the supernatant collected in step 2 was seeded (10 -1 ～10 -10 Multiple dilution) was used as an infection well, and two additional rows of negative control wells were provided. 100 mu L of virus filtrate or dilution of the virus dilution with a multiple ratio is added into the infection hole, and the virus is adsorbed for 1h at 37 ℃ and is gently shaken every 10min, so that the virus adsorption is ensured to be uniform. After 1h of adsorption, the supernatant was aspirated and the plate was gently washed 1 time with PBS. Adding virus maintenance solution, observing cytopathic effect every 12h after 48h, recording pathological hole number after 72h, and calculating TCID 50 Three replicates were assayed and the average was taken as the final viral titer.
Experimental knotAs shown in FIG. 4, the TCID of SVA is obtained after the IBRS-2 cells are treated with the compound KYP-2047 during the culturing process 50 Significantly reduced and dose dependent. It was shown that compounds KYP-2047 significantly reduced the viral titer of SVA and inhibited SVA replication.
Assay for SVA replication
The viral RNA copy number in the supernatant obtained in step 2 above was measured, and viral RNA replication analysis was performed.
The viral RNA replication assay steps are as follows: viral RNA in the harvested samples was extracted according to the protocol of the viral RNA extraction kit (OMEGA Co.) and fluorescent quantitative PCR amplification was performed using the one-step qPCR kit (TAKARA Co.) to detect the copy number of the RNA-dependent RNA replicase 3D gene of SVA.
qPCR reaction system: the total volume was 20. Mu.L, including 10. Mu.M of each of the upstream and downstream primers and the fluorescent-labeled probe, 0.4. Mu.L, 10. Mu.L of 2 XOne Step RT-PCR Buffer III, 0.4. Mu.L of TaKaRa Ex Taq HS (5U/. Mu.L), 0.4. Mu.L of PrimeScript RT Enzyme Mix II, 90ng of RNA 2. Mu.L, and 5.6. Mu.L of RNase Free dH 2O. The reaction conditions are as follows: 42 ℃, 5min,95 ℃, 10s,1cycle;95 ℃, 5s,60 ℃, 20s,40cycles.
Wherein the primer and probe sequences of qPCR are: upstream primer 5'-GCCAACGTCCCTTATCAACC-3', downstream primer 5'-CTAATGGCGTAGGGCAAACC-3', fluorescent labeled probe 5'-FAM-AGCAATCCTGGGCATCCCTGGA-TAMRA-3'.
The results are shown in FIG. 5, where RNA replication of SVA was significantly reduced and dose dependent following addition of compounds KYP-2047 during IBRS-2 cell culture. Compounds KYP-2047 were shown to significantly inhibit RNA replication of SVA. Expression of SVA structural protein VP1
And measuring the expression of the SVA structural protein VP2 in the cell sample, and carrying out virus structural protein expression level analysis.
The viral structural protein expression level analysis steps are as follows: IBRS-2 cells were counted and plated in 35mm dishes, after treatment of the experimental group with KYP-2047 (1 μm, 10 μm and 100 μm) at different concentrations for 4h and after treatment of the control group with DMSO (1%) for 4h when the cells were grown to 80% confluency; then SVA (MOI=0.1) was inoculated, the inoculation liquid was discarded 1h after inoculation, the cells were washed once with PBS, the maintenance liquid was supplemented, and the cells were harvested 12-14 h after inoculation, respectively. Taking a non-inoculated SVA strain as a Mock control; DMSO (without compounds KYP-2047) was used as a blank. Extracting total protein, and carrying out Western-blotting experiment to detect the expression difference of SVA VP2 protein.
As a result, as shown in FIG. 6, the expression of SVA structural protein VP2 was significantly reduced and dose-dependent after the addition of compounds KYP-2047 during the IBRS-2 cell culture. It is shown that compounds KYP-2047 significantly inhibit the expression of SVA structural protein VP2, and inhibit replication and infection of SVA.
Example 3 cytotoxicity of Compounds KYP-2047
Toxicity of small molecule compounds KYP-2047 to cells was tested using the CCK-8 assay. IBRS-2 cells (2X 10) were prepared in 96-well plates with DMEM+10% FBS medium 5 Well), cell culture medium was discarded, KYP-2047 (1. Mu.M, 2. Mu.M, 5. Mu.M, 8. Mu.M, 10. Mu.M, 20. Mu.M, 50. Mu.M, 80. Mu.M, 100. Mu.M) was added to the wells, while blank wells (containing cell culture medium alone), control wells (containing cells and medium) were set, 10. Mu.L of CCK-8 solution was added to each well of the cell plate after 24h incubation of the plate in the incubator, the plates were incubated in the incubator for 1-4 hours, and gentle mixing on a shaker was possible before reading the plates. The absorbance at 450nm was then measured with an enzyme-labeled instrument to calculate the cell viability.
As shown in FIG. 7, the compounds KYP-2047 have low cytotoxicity, and even when the dosage reaches 100 μm, the cell activity can still reach more than 90%, so that the cytotoxicity is low and the safety is good.
In summary, the embodiment of the invention takes host cell IBRS-2 as an example, and researches prove that the compound KYP-2047 can inhibit the replication of FMDV and SVA in the host cell IBRS-2, and the compound KYP-2047 can inhibit the replication of FMDV and SVA, and can be used for preparing medicaments or adjuvants for resisting FMDV and SVA virus infection.
The picornaviridae mainly includes the following five genera: enterovirus, rhinovirus, cardiovirus, aphtha, saikovirus, and FMDV belong to aphtha, SVA belongs to saikovirus. Due to the high degree of conservation of viral structural proteins between the four genera of the picornaviridae. Although the invention takes FMDV and SVA of picornaviridae viruses as examples, the compounds KYP-2047 prove that the invention can inhibit the replication of FMDV and SVA, but the invention is not limited to FMDV and SVA, and on the basis that the compounds KYP-2047 can inhibit the replication of FMDV and SVA, the invention can also inhibit the replication of other viruses of picornaviridae, and can also be used for inhibiting the replication of other viruses, and preparing medicaments or adjuvants for resisting viral infection.
Claims (4)
1. The application of compounds KYP-2047 in preparing medicaments for preventing virus infection, wherein the structural formula of the compounds KYP-2047 is shown as the following formula (I):
the virus is foot-and-mouth disease virus or saikaki virus.
2. Use of compounds KYP-2047 in the manufacture of a medicament for the treatment of viral infections, wherein the structural formula of said compounds KYP-2047 is shown as formula (i):
the virus is foot-and-mouth disease virus or saikaki virus.
3. The use according to claim 1 or 2, wherein the compound KYP-2047 is formulated into any pharmaceutically acceptable dosage form by adding pharmaceutically acceptable carriers and/or adjuvants.
4. The use according to claim 3, wherein the dosage form comprises a powder for injection, a capsule, a tablet, a suspension.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1533776A (en) * | 2003-03-27 | 2004-10-06 | 中国人民解放军第三军医大学 | Application of N-acetly glucosamine in the preparation of medicine for treating local injury and full body syndrome due to virus or bacterial infestation |
| CN113817019A (en) * | 2021-09-09 | 2021-12-21 | 集美大学 | Prolyl endopeptidase natural inhibitor and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1533776A (en) * | 2003-03-27 | 2004-10-06 | 中国人民解放军第三军医大学 | Application of N-acetly glucosamine in the preparation of medicine for treating local injury and full body syndrome due to virus or bacterial infestation |
| CN113817019A (en) * | 2021-09-09 | 2021-12-21 | 集美大学 | Prolyl endopeptidase natural inhibitor and preparation method and application thereof |
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