CN115137736A - Medicine for resisting African swine fever virus and screening method thereof - Google Patents
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Abstract
The invention relates to the technical field of medicines, in particular to an African swine fever virus resistant medicine and a screening method thereof. A drug for resisting African swine fever virus is cytarabine. The invention has the advantages that: (1) Has high antiviral ability and remarkable antiviral activity. (2) Low cytotoxicity, high selectivity coefficient and good safety.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an African swine fever virus resistant medicine and a screening method thereof.
Background
African Swine Fever Virus (ASFV) was determined in Kenyan of African countries at the earliest 20 th century in the 20 th century, and the epidemic situation was developed in the continental Europe, and through decades of efforts, the epidemic situation in mid-term Europe in the 20 th 90 th century was almost eliminated, but was developed again in 2007 and introduced into China in 8 months in 2018, and the first African Swine Fever epidemic situation was confirmed in Shenyang City of Liaoning province. Subsequently, epidemic situations occur in the provinces of Henan, jiangsu, zhejiang and Anhui in China successively, the economic loss is estimated to exceed one trillion yuan initially, and the method brings a huge impact to the pig industry in China. China is the first major world for live pig production, live pig breeding scale and pork consumption are the first world, and the number of stockings and the number of produced stockings exceed 50% of the world. The pig raising industry is also the supporting industry of the animal husbandry in China, and accounts for over 40 percent. The occurrence of the epidemic situation of the African swine fever brings a serious challenge to the swine industry in China, but at present, no effective vaccine or effective medicine is available, and the search for the medicine capable of preventing and controlling the African swine fever virus has great value.
The African Swine Fever Virus (ASFV) is a double-stranded DNA virus with a complex structure, which structurally comprises 5 layers of an outer membrane, a capsid, a double-layer inner membrane, a core shell layer, a genome and the like, contains more than 3 ten thousand protein subunits and forms a virus spherical particle with the diameter of about 260 nm. DNA replication is one of the most important mechanisms for maintaining the reproduction and survival of all organisms, including viruses, and is essentially the generation of two copies of genetic information by replicating DNA. This complex biological process is catalyzed by DNA polymerase (polymerase): under the direction of the template, single nucleotides are added to a growing primer. In many disease states, uncontrolled or overactive DNA replication can lead to the development and progression of cancer, autoimmune diseases, and viral/bacterial infections. The development of drugs targeting DNA polymerases is an important research direction in the biomedical field today.
Currently available DNA polymerase inhibitors are mainly nucleoside/nucleic acid analogs. These drugs are absorbed by organisms and converted to the triphosphate form, a compound similar to a mononucleotide (dNTP), by a series of metabolic-related enzymes. When the compound is integrated into a DNA chain by DNA polymerase serving as a raw material unit, the DNA chain is not extended any more due to the difference of chemical structures or induced spatial conformations, and the synthesis process is terminated, thereby playing the role of antivirus. This inhibition mechanism is also figuratively referred to as the "trojan horse" strategy.
This strategy has been applied to screening of african swine fever virus drugs, as early as 1986, and the Clercq research group in belgium reported the screening work of anti-ASFV nucleoside analogs in Vero cell model. Of the 8 compounds, (S) -HPMPA showed the best antiviral activity (MIC) 50 =0.01 μ g/mL), followed by C-C3Ado (MIC) 50 =0.025 μ g/mL) and pyrazofurin (MIC) 50 =1 μ g/mL). Subsequent mechanistic studies have shown that (S) -HPMPA specifically and concentration-dependently inhibits ASFV virus DNA synthesis and also has a significant inhibitory effect on the production of viral proteins, especially IP-73.
Cytarabine was approved by the FDA as a human anticancer drug as early as 1969, and up to now, cytarabine has been approved for the treatment of Acute Myeloid Leukemia (AML), acute Lymphocytic Leukemia (ALL), chronic Myeloid Leukemia (CML), and non-hodgkin's lymphoma. In addition to anticancer indications, cytarabine also has antiviral activity as a DNA polymerase inhibitor as well as a DNA synthesis inhibitor. Because of the low oral bioavailability (< 20%), cytarabine must be injected to be effective, the dose specification sold on the market at present is 20mg/mL or 100mg/5mL, the plasma protein binding rate is 13%, the half-life is 10min, and the metabolism is mainly performed by the liver. Cytarabine is currently listed in the world health organization's list of essential drugs because of its highly effective therapeutic effect and high safety.
Aiming at the problem that the African swine fever virus does not have an effective vaccine or an effective medicament at present, the method for searching the medicament capable of preventing and controlling the African swine fever virus has great value.
Disclosure of Invention
The invention aims to provide a drug for resisting African swine fever virus with obvious antiviral activity and good safety and a screening method thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a medicine for resisting African swine fever virus is cytarabine with the structure of
Further, the medicine is used for resisting the African swine fever virus infection.
Further, the administration mode of the medicine is injection.
The invention also provides application of cytarabine as a medicament for resisting African swine fever virus
Use of cytarabine as a medicament against African swine fever virus.
The invention also provides the application of the salt form, hydrate, solvate and isotope substitute of the cytarabine.
Salt form, hydrate, solvate and isotope substitute of cytarabine are used as the medicine for resisting African swine fever virus.
The invention also provides the application of another salt type, hydrate, solvate and isotope substituent of the cytarabine.
Salt form, hydrate, solvate and isotope substitute of cytarabine are used as African swine fever virus DNA polymerase inhibitors.
The invention also provides a pharmaceutical composition for resisting African swine fever virus.
One of the active ingredients of the pharmaceutical composition is cytarabine.
The invention also provides the application of the pharmaceutical composition of which one of the effective components is cytarabine.
The application of the pharmaceutical composition of which one of the effective components is cytarabine as a medicine for resisting African swine fever virus.
The invention also provides a screening method of the African swine fever virus resistant medicine.
A screening method of an African swine fever virus resistant drug, which comprises the following steps:
s101, constructing an ASFV DNA polymerase model, identifying a DNA polymerase sequence, preparing an ASFV DNA polymerase full-length protein sequence template, calibrating a sequence, modeling homology, and evaluating the quality of the homology model;
s102, performing multiple rounds of screening on the candidate drugs according to the virus DNA synthesis inhibition rate, the cell activity and the selection coefficient in sequence;
s103, constructing a DNA polymerase retention model of ASFV in S101 by screening the obtained drugs in step S102.
Further, in step S102, the inhibition rate of viral DNA synthesis is the first round of screening, and the screening standard is that the inhibition rate of DNA is greater than 50%.
Further, in step S102, a second round of screening is performed according to the cell activity, and the screening criteria is that the cell activity is greater than 80% and is dose-dependent.
Further, in step S102, the selection coefficient SI of the candidate drug passing through the second round is determined.
The invention provides a drug for resisting African swine fever virus, and provides an application of cytarabine in a drug for resisting African swine fever virus. The African swine fever virus resisting medicine has low cytotoxicity, high antiviral capacity and high selection coefficient, and may be used in preventing and treating African swine fever virus effectively.
The screening method of the African swine fever virus resistant medicine provided by the invention is implemented by the in vitro antiviral ability (IC) of DNA polymerase inhibitor and DNA synthesis inhibitor approved by FDA 50 ) Screening and toxicity (CC) of the drug on Normal cells (porcine alveolar macrophages) 50 ) Screening to obtain the medicine with obvious antiviral capacity and high selection coefficient, and can be used for blocking an African swine fever virus epidemic area and preventing and treating diseases.
Compared with the prior art, the invention provides a drug for resisting African swine fever virus and a screening method thereof, and the drug has the advantages that:
(1) Has high antiviral ability and remarkable antiviral activity.
(2) Low cytotoxicity, high selectivity coefficient and good safety.
Drawings
FIG. 1 is an alignment of the DNA polymerase protein sequences of ASFV provided by the present invention;
FIG. 2 is a schematic diagram showing a DNA polymerase homology modeling model of the constructed ASFV;
FIG. 3 shows the structural formula of cytarabine.
FIG. 4 structural formula of triphosphorylated cytarabine.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the following examples further describe the present invention in detail, and the following examples are only used for illustrating the present invention, but not to limit the scope of the present invention.
The drug is cytarabine and has the following structure
Further, the medicine is used for resisting the African swine fever virus infection.
Further, the administration mode of the medicine is injection.
The invention also provides application of cytarabine as a medicament for resisting African swine fever virus
Use of cytarabine as a medicament against African swine fever virus.
The invention also provides the application of the salt form, hydrate, solvate and isotope substitute of the cytarabine.
Salt form, hydrate, solvate and isotope substitute of cytarabine are used as the medicine for resisting African swine fever virus.
The invention also provides the application of another salt type, hydrate, solvate and isotope substituent of the cytarabine.
Salt form, hydrate, solvate and isotope substitute of cytarabine are used as African swine fever virus DNA polymerase inhibitors.
The invention also provides a pharmaceutical composition for resisting African swine fever virus.
One of the active ingredients of the pharmaceutical composition is cytarabine.
The invention also provides the application of the pharmaceutical composition of which one of the effective components is cytarabine.
The application of the pharmaceutical composition with one of the active ingredients of cytarabine as a medicament for resisting African swine fever virus.
The invention also provides a screening method of the African swine fever virus resistant medicine.
A screening method of a drug for resisting African swine fever viruses, which comprises the following steps:
s101, constructing an ASFV DNA polymerase model, identifying a DNA polymerase sequence, preparing an ASFV DNA polymerase full-length protein sequence template, calibrating a sequence, modeling homology, and evaluating the quality of the homology model;
s102, performing multiple rounds of screening on the candidate drugs according to the virus DNA synthesis inhibition rate, the cell activity and the selection coefficient in sequence;
s103, constructing a DNA polymerase retention model of ASFV in S101 by screening the obtained drugs in step S102.
Further, in step S102, the inhibition rate of viral DNA synthesis is the first round of screening, and the screening standard is that the inhibition rate of DNA is greater than 50%.
Further, in step S102, a second round of screening is performed according to the cell activity, and the screening criteria is that the cell activity is greater than 80% and is dose-dependent.
Further, in step S102, the selection coefficient SI of the candidate drug passing through the second round is determined.
Example 1
A drug for resisting African swine fever virus is cytarabine.
Cytarabine is used for resisting African swine fever virus infection.
The administration mode of the cytarabine is injection, including but not limited to intravenous injection, subcutaneous injection and intramuscular injection.
Cytarabine and its salt form, hydrate, solvate and isotope substitute can be used as medicine for resisting African swine fever virus.
One of the active ingredients is the medicinal composition of the cytarabine which is used as a medicament for resisting African swine fever virus.
Example 2
Cytarabine and salt forms, hydrates, solvates and isotope substitutes thereof are used as African swine fever virus DNA polymerase inhibitors.
Example 3
S101: construction of a DNA polymerase model for ASFV: DNA polymerase sequence identification, preparation of ASFV DNA polymerase full-length protein sequence template, sequence calibration and homology modeling, and homology model quality evaluation.
The DNA polymerase of the ASFV is B-type DNA polymerase, the polymerase takes deoxynucleotide as raw material to synthesize virus DNA, the coding gene is G1211R (UniProt ID: P42489), and the virus DNA is downloaded from UniProt (http:// www.uniprot.org) and stored in FASTA format.
The full-length protein sequence template of the ASFV DNA polymerase is a human polymerase delta holoenzyme (PDB ID:6S 1M) which is searched from PDB bank and has the highest matching degree with G1211R, and is sorted according to the matching length (726 bases), the coincidence rate (159 in 726) and the positive rate (294 in 726). The PDB format was downloaded and introduced into the molecular operating environment (MOE, version 2019), retaining the a strand (DNA polymerase delta catalytic subunit), the P strand (DNA primer), the T strand (DNA template) and thymidine-5' -triphosphate.
The sequence calibration is as follows: the ASFV DNA polymerase gene (UniProt ID: P42489) was introduced into MOE, and the alignment was carried out using a template (6S1M, strand A) to calculate the degree of sequence overlap and similarity.
The homology modeling is carried out according to a standard homology modeling program, a P chain, a T chain and thymidine-5' -triphosphate are used as construction environments, C-terminal modeling and N-terminal modeling are blocked, and an intermediate model is generated by sampling a main chain and a side chain. Fine tuning was performed by a force field Amber12 EHT. The final model was determined by adding hydrogen via Protonate 3D. The final model was determined based on the Generalized Born/Volume Integral (GB/VI) electrostatic solvation energies.
The quality evaluation of the homologous modeling is carried out through a protein geometric module in the MOE, and the Phi-psi angle, the bond length, the bond angle, the dihedral angle and the atomic collision are all evaluation indexes.
S102: carrying out multiple rounds of screening on candidate drugs according to the virus DNA synthesis inhibition rate, cell activity and selection coefficient in sequence;
the first round of screening according to the virus DNA synthesis inhibition rate has the screening standard that the DNA replication inhibition rate is more than 50 percent.
And the second round of screening according to the cell activity is carried out, wherein the screening standard is that the second round of screening is carried out on the compound with lower toxicity, namely the cell activity is more than 80%, and the second round of screening is dose-dependent.
The third round of screening is to perform CC on the candidate drugs screened by the second round 50 (drug concentration at 50% Normal cell death) and IC 50 (concentration of drug inhibiting 50% of virus replication) and the ratio thereof was calculated to obtain the selection coefficient SI. The specific implementation steps are as follows: for screening and obtaining the drug capable of inhibiting replication of African Swine Fever Virus (ASFV) with expression reporter gene GFP inserted at 4 × 10 5 The cells were inoculated with Porcine Alveolar Macrophages (PAM) at a density per well in 96-well plates and incubated for 24h. Is carried out with a 1Multiplicity Of Infection (MOI)ASFV-GFP was infected, then treated with DNA polymerase inhibitors at a final concentration of 10mM for 1 hour, and then culture supernatants were removed, observed by a fluorescence microscope after 24 hours and 48 hours, and three rounds of selection were performed with only the infected group as a control: the first round screens out the medicines with the inhibition rate of more than 50 percent, the second round screens out the medicines screened out in the first round again, and the standard cell activity is judged to be more than 80 percent and is in dose dependence; the third round of screening carries out drug CC according to the results of the previous round of screening 50 (drug concentration at 50% Normal cell death), IC 50 (concentration of drug inhibiting 50% of viral replication) and the selection coefficient SI = CC was calculated 50 /IC 50 The method preliminarily determines the medicine with good safety and good ASFV proliferation inhibiting effect.
Through the screening, as shown in table 1, cytarabine has remarkable antiviral activity and good safety.
TABLE 1 pharmacological parameters in cytarabine resistance to ASFV
The cytarabine single drug and the pharmaceutical composition thereof can be used for treating ASFV infection, wherein: cytarabine has the structural formula:
the cytarabine is used as a single medicine, and a salt form, a hydrate, a solvate or an isotope substitute thereof is used for preparing the anti-African swine fever virus medicine.
The cytarabine is used as an effective component in the pharmaceutical composition and is used for preparing the medicament for resisting African swine fever virus.
S103: step S102, constructing a DNA polymerase retention model of the ASFV in step 1 by the screened cytarabine.
The cytarabine and the triphosphate the 3D structure of cytarabine is selected from PubChem (C:)https:// pubchem.ncbi.nlm.nih.gov/) ExportingMOE was introduced and calibrated by thymidine-5' -triphosphate. The base pair of the DNA template strand is mutated to deoxyguanosine (dG). Finally, the base-modified model except for the adjacent bases of the arabinoside triphosphate is adjusted to the lowest energy form, and the arabinoside triphosphate and the DNA polymerase or DNA strand of ASFV are analyzed.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various changes may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are included in the protective scope of the present invention.
It should be noted that, in the foregoing embodiments, various specific technical features and steps described in the above embodiments can be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations of the features and steps are not described separately.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (9)
1. Application of cytarabine and salt forms, hydrates, solvates and isotope substitutes thereof in preparing medicaments for preventing or treating African swine fever virus.
2. Use of cytarabine and its salt form, hydrate, solvate and isotope substitute in preparation of African swine fever virus DNA polymerase inhibitor is provided.
3. The application of the cytarabine serving as the only active ingredient in preparing the medicament for preventing or treating the African swine fever virus or the application in preparing the African swine fever virus DNA polymerase inhibitor.
4. Use according to claims 1-3, characterized in that the medicament is an injection.
5. The use according to claim 4, wherein the injection is administered intravenously, subcutaneously or intramuscularly.
6. A screening method of an anti-African swine fever virus medicine is characterized by comprising the following steps:
s101, constructing an ASFV DNA polymerase model, identifying a DNA polymerase sequence, preparing an ASFV DNA polymerase full-length protein sequence template, calibrating a sequence, modeling homology, and evaluating the quality of the homology model;
s102, performing multiple rounds of screening on the candidate drugs according to the virus DNA synthesis inhibition rate, the cell activity and the selection coefficient in sequence;
s103, constructing a DNA polymerase retention model of ASFV in S101 by screening the obtained drugs in step S102.
7. The screening method of claim 6, which is characterized in that: in step S102, the inhibition rate of viral DNA synthesis is the first round of screening, and the screening standard is that the inhibition rate of DNA is greater than 50%.
8. The screening method of claim 7, wherein the screening method comprises the following steps: in step S102, a second round of screening is performed according to the cell activity, and the screening criteria is that the cell activity is greater than 80% and is dose-dependent.
9. The screening method of claim 8, wherein the screening method comprises the following steps: in step S102, the selection coefficient SI of the candidate drug passing through the second round is determined.
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