CN111991559B - Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection - Google Patents
Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection Download PDFInfo
- Publication number
- CN111991559B CN111991559B CN202010917293.5A CN202010917293A CN111991559B CN 111991559 B CN111991559 B CN 111991559B CN 202010917293 A CN202010917293 A CN 202010917293A CN 111991559 B CN111991559 B CN 111991559B
- Authority
- CN
- China
- Prior art keywords
- novel coronavirus
- cov
- tyrosine kinase
- receptor tyrosine
- sars
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention belongs to the field of antiviral drugs, and discloses application of a receptor tyrosine kinase inhibitor in preparation of a drug for preventing and/or treating novel coronavirus infection. The receptor tyrosine kinase inhibitors such as masitinib, erlotinib, and rocitinib can extremely strongly inhibit the synthesis of SARS-CoV-2 replicon RNA of the novel coronavirus and reduce the RNA copy quantity of the wild type SARS-CoV-2 of the novel coronavirus in cells, thereby inhibiting the replication of the novel SARS-CoV-2 of the coronavirus, and having the effect of preventing and/or treating the infection of the novel SARS-CoV-2 of the coronavirus.
Description
Technical Field
The invention relates to the field of antiviral drugs, in particular to application of a receptor tyrosine kinase inhibitor in preparing a drug for preventing and/or treating novel coronavirus infection.
Background
Since the outbreak of the novel coronavirus disease COVID-19 in 2019, the disease has spread rapidly worldwide, causing a huge global economic and medical burden. By day 5/8 of 2020, the global cumulative report corroboration cases of 18,543,662 and the cumulative death cases of 700,714 were shown based on data from john hopkins university, usa.
At present, no specific medicine is available for 2019 coronavirus diseases, and the existing treatment is mostly symptomatic treatment and cannot effectively reverse the progress of the disease course of a severe patient. The new type coronavirus is partially similar to SARS-CoV and MERS-CoV, but is completely different, and partial patients have poor effect after antiviral and anti-inflammatory treatment, and are easy to have infection, thus causing multiple and diffuse lesions. Therefore, the research of targeted drugs aiming at the target of the novel coronavirus is of great significance.
Receptor tyrosine kinase inhibitors can block intracellular domain activation signals after cell surface receptors are combined with ligands through inhibition of the activity (reversible or irreversible) of the receptor tyrosine kinase, thereby inhibiting the final biological effect of signal transfer to a pathway. Common receptor tyrosine kinase inhibitors are Masitinib (Masitinib), erlotinib (Alectonib), and rocitinib (Rociletinib).
Wherein, the masitinib is a specific C-Kit inhibitor and is mainly used for treating gastrointestinal stromal tumors caused by C-Kit mutation (Gain of function). But now also begin to be used for the treatment of asthma, multiple sclerosis, and mast cell leukemia (mast cell leukemia) because it can inhibit the activity of mast cells.
The structural formula (I) of the masitinib is shown as follows:
the erlotinib is a tyrosine kinase inhibitor of ALK (IC50 is 1.9nmol/L) and RET (IC50 is 4.8nmol/L), and is found in non-clinical studies to inhibit the phosphorylation process of ALK and the activation of ALK-mediated downstream signal proteins STAT3 and AKT, and reduce the survival rate of cell strains with ALK protein fusion, proliferation or mutation activation capacity. Eltaminib is the 3 rd drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALK-positive NSCLC following crizotinib (crizotinib) and ceritinib (ceritinib). The advantages of erlotinib are not only effective in advanced disease progression or drug resistant (metastatic) ALK-positive NSCLC after treatment with crizotinib, but also in shrinkage of brain tumors in patients with brain metastases. Allertib belongs to the group of 2 nd generation anaplastic lymphoma kinase (anaplastic lymphoma kinase, ALk) inhibitors, and is used for treating ALK gene mutation patients with advanced non-small cell lung cancer.
(II) the structural formula (II) of elotinib:
rocitinib is a drug used for treating non-small cell lung cancer with specific mutations. Is a third generation epidermal growth factor receptor tyrosine kinase inhibitor. Rocetitinib (Rociletinib) can inhibit the activity of EGFR-L858R/T790M and EGFR WT. IC50 values were 21.5nM and 303.3nM, respectively.
Rocitinib represented by structural formula (III):
the above receptor tyrosine kinase inhibitors have good effects on various diseases, but at present, no relevant report that the receptor tyrosine kinase inhibitors are applied to preventing and/or treating novel coronavirus infection exists.
Disclosure of Invention
The invention provides application of receptor tyrosine kinase inhibitors such as masitinib, erlotinib, rocitinib and the like or pharmaceutically acceptable salts of the small molecular compounds in preparation of medicaments for preventing and/or treating novel coronavirus SARS-CoV-2 infection, aiming at the problem that the infection caused by the novel coronavirus SARS-CoV-2 is lack of effective prevention and treatment medicaments at present. The invention utilizes the novel coronavirus SARS-CoV-2 safety replicon and the separated wild-type novel coronavirus SARS-CoV-2, and cell experiments prove that receptor tyrosine kinase inhibitors such as masitinib, Aleptinib, Rocetitinib and the like can inhibit RNA synthesis of the virus and prevent transcription and replication of the virus. Therefore, the receptor tyrosine kinase inhibitors such as masitinib, masitinib and rositinib have the effects of preventing and/or treating novel coronavirus infection, and can be prepared into medicaments related to preventing and/or treating novel coronavirus infection for application.
The second purpose of the invention is to provide the application of the receptor tyrosine kinase inhibitor in preparing the medicine for preventing and/or treating the novel coronavirus inflammation.
The third purpose of the invention is to provide the application of receptor tyrosine kinase inhibitor in preparing novel coronavirus RNA synthesis inhibitor.
It is a fourth object of the present invention to provide a medicament for the prevention and/or treatment of novel coronavirus infections.
The above object of the present invention is achieved by the following scheme:
use of a receptor tyrosine kinase inhibitor for the preparation of a medicament for the prevention and/or treatment of a novel coronavirus infection.
Further, the receptor tyrosine kinase inhibitor is selected from at least one of masitinib, erlotinib, and rositinib, and pharmaceutically acceptable salts thereof.
Further, the novel coronavirus is a 2019 novel coronavirus (2019-nCoV, SARS-CoV-2).
Use of a receptor tyrosine kinase inhibitor for the preparation of a medicament for the prevention and/or treatment of novel coronavirus inflammation.
Further, the receptor tyrosine kinase inhibitor is selected from at least one of masitinib, erlotinib, and rositinib, and pharmaceutically acceptable salts thereof.
Further, the novel coronavirus inflammation is novel coronavirus pneumonia (COVID-19).
Use of a receptor tyrosine kinase inhibitor for the preparation of a novel inhibitor of coronavirus RNA replication.
Further, the novel coronavirus is a 2019 novel coronavirus (2019-nCoV, SARS-CoV-2).
A medicament for the prophylaxis and/or treatment of a novel coronavirus infection, comprising a receptor tyrosine kinase inhibitor.
Further, the receptor tyrosine kinase inhibitor is selected from at least one of masitinib, erlotinib, and rositinib, and pharmaceutically acceptable salts thereof.
Further, the medicine is capsule, tablet, pill, granule, electuary, injection or spray.
Further, the medicine can also comprise pharmaceutically acceptable auxiliary materials or carriers.
Further, the medicament may also comprise other anti-coronavirus medicaments.
Further, the medicament may further comprise a component for enhancing the immunological competence of the human body.
When receptor tyrosine kinase inhibitors such as masitinib, erlotinib, and roxitinib or pharmaceutically acceptable salts of the above drugs inhibit the replication of the novel coronavirus, other anti-coronavirus drugs are adopted to inhibit the existing novel coronavirus, the immunity of a human body is improved, and the inhibition and removal of the novel coronavirus by the human body are enhanced, so that the aim of removing the novel coronavirus is fulfilled.
Compared with the prior art, the invention has the following beneficial effects:
the receptor tyrosine kinase inhibitor is applied to preventing and/or treating novel coronavirus infection for the first time, and the receptor tyrosine kinase inhibitors such as masitinib, erlotinib, and roxitinib can strongly inhibit the transcription and replication of novel coronavirus RNA so as to inhibit the replication of the novel coronavirus, so that the receptor tyrosine kinase inhibitors such as masitinib, erlotinib, and roxitinib or pharmaceutically acceptable salts thereof have the effect of preventing and/or treating the novel coronavirus infection, and can be prepared into a novel coronavirus resistant medicament for application; meanwhile, the medicine can be applied together with other anti-coronavirus medicines and medicines for enhancing the immunity of human bodies, so that the curative effect is further enhanced.
Drawings
FIG. 1 shows the inhibitory effect of masitinib, erlotinib, and roxitinib on RNA synthesis of SARS-CoV-2 safe replicons;
FIG. 2 shows the inhibition of wild-type SARS-CoV-2 replication by masitinib, erlotinib, and roxitinib.
Detailed Description
The invention is described in further detail below with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
The SARS-CoV-2 safety replicon can simulate RNA transcription and replication of SARS-CoV-2 in cells, and the luciferase activity in the cells can directly reflect the RNA transcription and replication degree of SARS-CoV-2, and at the same time, can not produce infectious novel coronavirus SARS-CoV-2. Therefore, the invention utilizes the novel coronavirus SARS-CoV-2 safety replicon to verify the inhibition effect of masitinib, erlotinib and roxitinib on the RNA synthesis of SARS-CoV-2.
The related experiments can be carried out in a P2 laboratory, and the specific experimental steps are as follows:
SARS-CoV-2 safety replicon-constituting plasmids ps2V (SEQ ID NO: 1), ps2AN (SEQ ID NO: 2), ps2AC (SEQ ID NO: 3), ps2B (SEQ ID NO: 4) were transfected in a proportion using Lipo2000 transfection reagent from Thermo Fisher and Opti-MEM into HEK293T cells (cell density of about 6.5X 10) grown on 12-well cells treated with polylysine one day in advance4/cm2) The amounts of reagents are shown in Table 1 below. Specifically, 100. mu.L of Opti-MEM was used to dissolve the plasmid, and 100. mu.L of LOpti-MEM was used to dissolve Lipo2000, and after incubation for 5min, the plasmids were mixed, and after further incubation for 20min, HEK293T cells were added.
TABLE 1 Opti-Lipo2000-DNA mixture System
6h after transfection, masitinib or erlotinib or roxitinib was added according to a concentration gradient (20. mu.M, 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M, 0.625. mu.M, 0.3125. mu.M, 0.15625. mu.M, 0.078125. mu.M, 0.0390625. mu.M). After 24h drug treatment, luciferase activity of the cells was measured, inhibition was calculated based on DMSO control, and half-inhibitory concentration of the drug (hereinafter referred to as IC50) was counted using Graphpad Prism 7.0 software. The experiment was repeated for 3 sets of concentrations and the data obtained are shown in table 2 below, and the data from table 2 were processed to obtain the curve shown in figure 1.
TABLE 2 inhibition of masitinib, erlotinib, and roxitinib at different concentrations
The results in FIG. 1 and Table 2 show that masitinib, erlotinib and roxitinib have inhibitory effects on RNA synthesis of SARS-CoV-2, wherein the IC50 of masitinib is 0.6521 + -0.0661 μ M, the IC50 of erlotinib is 0.5639 + -0.0175 μ M, and the IC50 of roxitinib is 7.319 + -1.210 μ M, which indicates that masitinib, erlotinib and roxitinib can inhibit the transcription and replication of novel coronavirus RNA and have therapeutic effects on the infection of novel coronavirus.
Example 2
The invention utilizes separated wild type novel coronavirus SARS-CoV-2 to verify the inhibition effect of masitinib, erlotinib and roxitinib on virus replication, and the specific experimental method is as follows:
HEK293T cells in good growth were plated on average in 48-well plates treated with polylysine (cell density approximately 6.5X 10)4/cm2). After the cells had grown for 16h (cell density about 1.6X 10)5mL), 0.1 μ g of the pCMV-ACE2-FLAG plasmid expressing the SARS-CoV-2 receptor ACE2 purchased from beijing yinqiao china. 24h after transfection, cells were washed with PBS and infected with wild-type SARS-CoV-2(MOI 0.1, 37 ℃, 1 h). Subsequently, DMEM (2% FBS) containing different concentration gradients (20. mu.M, 5. mu.M, 1.25. mu.M, 0.3125. mu.M, 0.078125. mu.M, 0.01953125. mu.M) of masitinib or erlotinib or rocatinib drug was replaced. After 24h of drug treatment, cellular RNA was extracted using TRIZOL. Novel coronavirus 201 utilizing Daan gene for RNA copy of SARS-CoV-2And (3) detecting the 9-nCOV nucleic acid (PCR-fluorescence probe method) to obtain a Ct value, calculating the virus copy number according to a standard curve, calculating the inhibition rate, and counting the IC50 of the medicine by using Graphpad Prism 7.0 software.
The experiment was repeated for 3 groups at each concentration and the data obtained are shown in table 3 below, and the data from table 3 were processed to obtain the curve shown in figure 2.
TABLE 3 inhibition of masitinib, erlotinib, and roxitinib at different concentrations
As can be seen from the test results of FIG. 2 and Table 3, masitinib, Alertinib and Rocetitinib can reduce the RNA copy amount of wild-type new coronavirus SARS-CoV-2 in the cells and inhibit the growth of wild-type SARS-CoV-2. In inhibiting the growth of wild type SARS-CoV-2, the IC50 of masitinib is 0.597 + -0.341. mu.M, the IC50 of erlotinib is 0.1396 + -0.0913. mu.M, and the IC50 of rocitinib is 11.25 + -1.89. mu.M. The experimental results further show that masitinib, erlotinib and roxitinib can inhibit the transcription and replication of the RNA of the novel coronavirus, and have a therapeutic effect on the infection of the novel coronavirus.
SEQUENCE LISTING
<110> Zhongshan university
Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection
<130>
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 4364
<212> DNA
<213> Artificial sequence
<400> 1
gctagcatta aaggtttata ccttcccagg taacaaacca accaactttc gatctcttgt 60
agatctgttc tctaaacgaa ctttaaaatc tgtgtggctg tcactcggct gcatgcttag 120
tgcactcacg cagtataatt aataactaat tactgtcgtt gacaggacac gagtaactcg 180
tctatcttct gcaggctgct tacggtttcg tccgtgttgc agccgatcat cagcacatct 240
aggtttcgtc cgggtgtgac cgaaaggtaa ggtggagagc cttgtccctg gtttcaacga 300
gaaaacacac gtccaactca gtttgcctgt tttacaggtt cgcgacgtgc tcgtacgtgg 360
ctttggagac tccgtggagg aggtcttatc agaggcacgt caacatctta aagatggcac 420
ttgtggctta gtagaagttg aaaaaggcgt tttgcctcaa cttgaacagc ctgagctttg 480
ggctaagcgc aacattaaac cagtaccaga ggtgaaaata ctcaataatt tgggtgtgga 540
cattgctgct aatactgtga tctgggacta caaaagagat gctccagcac atatatctac 600
tattggtgtt tgttctatga ctgacatagc caagaaacca actgaaacga tttgtgcacc 660
actcactgtc ttttttgatg gtagagttga tggtcaagta gacttattta gaaatgcccg 720
taatggtgtt cttattacag aaggtagtgt taaaggttta caaccatctg taggtcccaa 780
acaagctagt cttaatggag tcacattaat tggagaagcc gtaaaaacac agttcaatta 840
ttataagaaa gttgatggtg ttgtccaaca attacctgaa acttacttta ctcagagtag 900
aaatttacaa gaatttaaac ccaggagtca aatggaaatt gatttcttag aattagctat 960
ggatgaattc attgaacggt ataaattaga aggctatgcc ttcgaacata tcgtttatgg 1020
agattttagt catgagggcc cggaaacctg gccctgtctt cttgacgagc attcctaggg 1080
gtctttcccc tctcgccaaa ggaatgcaag gtctgttgaa tgtcgtgaag gaagcagttc 1140
ctctggaagc ttcttgaaga caaacaacgt ctgtagcgac cctttgcagg cagcggaacc 1200
ccccacctgg cgacaggtgc ctctgcggcc aaaagccacg tgtataagat acacctgcaa 1260
aggcggcaca accccagtgc cacgttgtga gttggatagt tgtggaaaga gtcaaatggc 1320
tctcctcaag cgtattcaac aaggggctga aggatgccca gaaggtaccc cattgtatgg 1380
gatctgatct ggggcctcgg tgcacatgct ttacatgtgt ttagtcgagg ttaaaaaaac 1440
gtctaggccc cccgaaccac ggggacgtgg ttttcctttg aaaaacacga tgataagcgg 1500
ccgcatggtg agcaagggcg aggagctgtt caccggggtg gtgcccatcc tggtcgagct 1560
ggacggcgac gtaaacggcc acaagttcag cgtgtccggc gagggcgagg gcgatgccac 1620
ctacggcaag ctgaccctga agttcatctg caccaccggc aagctgcccg tgccctggcc 1680
caccctcgtg accaccctga cctacggcgt gcagtgcttc agccgctacc ccgaccacat 1740
gaagcagcac gacttcttca agtccgccat gcccgaaggc tacgtccagg agcgcaccat 1800
cttcttcaag gacgacggca actacaagac ccgcgccgag gtgaagttcg agggcgacac 1860
cctggtgaac cgcatcgagc tgaagggcat cgacttcaag gaggacggca acatcctggg 1920
gcacaagctg gagtacaact acaacagcca caacgtctat atcatggccg acaagcagaa 1980
gaacggcatc aaggtgaact tcaagatccg ccacaacatc gaggacggca gcgtgcagct 2040
cgccgaccac taccagcaga acacccccat cggcgacggc cccgtgctgc tgcccgacaa 2100
ccactacctg agcacccagt ccgccctgag caaagacccc aacgagaagc gcgatcacat 2160
ggtcctgctg gagttcgtga ccgccgccgg gatcactctc ggcatggacg agctgtacaa 2220
gtaataataa taagatatct gatcttctgg tctaaacgaa ctaaatatta tattagtttt 2280
tctgtttgga actttaattt tagccatggc cgatgctaag aacattaaga agggccctgc 2340
tcccttctac cctctggagg atggcaccgc tggcgagcag ctgcacaagg ccatgaagag 2400
gtatgccctg gtgcctggca ccattgcctt caccgatgcc cacattgagg tggacatcac 2460
ctatgccgag tacttcgaga tgtctgtgcg cctggccgag gccatgaaga ggtacggcct 2520
gaacaccaac caccgcatcg tggtgtgctc tgagaactct ctgcagttct tcatgccagt 2580
gctgggcgcc ctgttcatcg gagtggccgt ggcccctgct aacgacattt acaacgagcg 2640
cgagctgctg aacagcatgg gcatttctca gcctaccgtg gtgttcgtgt ctaagaaggg 2700
cctgcagaag atcctgaacg tgcagaagaa gctgcctatc atccagaaga tcatcatcat 2760
ggactctaag accgactacc agggcttcca gagcatgtac acattcgtga catctcatct 2820
gcctcctggc ttcaacgagt acgacttcgt gccagagtct ttcgacaggg acaaaaccat 2880
tgccctgatc atgaacagct ctgggtctac cggcctgcct aagggcgtgg ccctgcctca 2940
tcgcaccgcc tgtgtgcgct tctctcacgc ccgcgaccct attttcggca accagatcat 3000
ccccgacacc gctattctga gcgtggtgcc attccaccac ggcttcggca tgttcaccac 3060
cctgggctac ctgatttgcg gctttcgggt ggtgctgatg taccgcttcg aggaggagct 3120
gttcctgcgc agcctgcaag actacaaaat tcagtctgcc ctgctggtgc caaccctgtt 3180
cagcttcttc gctaagagca ccctgatcga caagtacgac ctgtctaacc tgcacgagat 3240
tgcctctggc ggcgccccac tgtctaagga ggtgggcgaa gccgtggcca agcgctttca 3300
tctgccaggc atccgccagg gctacggcct gaccgagaca accagcgcca ttctgattac 3360
cccagagggc gacgacaagc ctggcgccgt gggcaaggtg gtgccattct tcgaggccaa 3420
ggtggtggac ctggacaccg gcaagaccct gggagtgaac cagcgcggcg agctgtgtgt 3480
gcgcggccct atgattatgt ccggctacgt gaataaccct gaggccacaa acgccctgat 3540
cgacaaggac ggctggctgc actctggcga cattgcctac tgggacgagg acgagcactt 3600
cttcatcgtg gaccgcctga agtctctgat caagtacaag ggctaccagg tggccccagc 3660
cgagctggag tctatcctgc tgcagcaccc taacattttc gacgccggag tggccggcct 3720
gcccgacgac gatgccggcg agctgcctgc cgccgtcgtc gtgctggaac acggcaagac 3780
catgaccgag aaggagatcg tggactatgt ggccagccag gtgacaaccg ccaagaagct 3840
gcgcggcgga gtggtgttcg tggacgaggt gcccaagggc ctgaccggca agctggacgc 3900
ccgcaagatc cgcgagatcc tgatcaaggc taagaaaggc ggcaagatcg ccgtgtaagg 3960
atccgtgggc tatataaacg ttttcgcttt tccgtttacg atatatagtc tactcttgtg 4020
cagaatgaat tctcgtaact acatagcaca agtagatgta gttaacttta atctcacata 4080
gcaatcttta atcagtgtgt aacattaggg aggacttgaa agagccacca cattttcacc 4140
gaggccacgc ggagtacgat cgagtgtaca gtgaacaatg ctagggagag ctgcctatat 4200
ggaagagccc taatgtgtaa aattaatttt agtagtgcta tccccatgtg attttaatag 4260
cttcttagga gaatgacaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa ctagcataac 4320
cccttggggc ctctaaacgg gtcttgaggg gttttttgtc taga 4364
<210> 2
<211> 10429
<212> DNA
<213> Artificial sequence
<400> 2
gctagcgagg gcccggaaac ctggccctgt cttcttgacg agcattccta ggggtctttc 60
ccctctcgcc aaaggaatgc aaggtctgtt gaatgtcgtg aaggaagcag ttcctctgga 120
agcttcttga agacaaacaa cgtctgtagc gaccctttgc aggcagcgga accccccacc 180
tggcgacagg tgcctctgcg gccaaaagcc acgtgtataa gatacacctg caaaggcggc 240
acaaccccag tgccacgttg tgagttggat agttgtggaa agagtcaaat ggctctcctc 300
aagcgtattc aacaaggggc tgaaggatgc ccagaaggta ccccattgta tgggatctga 360
tctggggcct cggtgcacat gctttacatg tgtttagtcg aggttaaaaa aacgtctagg 420
ccccccgaac cacggggacg tggttttcct ttgaaaaaca cgatgataaa tggagtccct 480
ggtgcccggc ttcaacgaga agacccacgt gcagctgtct ctgcctgtgc tgcaggtgag 540
ggatgtgctg gtgcgcggct ttggcgactc cgtcgaggag gtgctgtctg aggccaggca 600
gcacctgaag gacggaacct gcggactggt ggaggtggag aagggcgtgc tgccacagct 660
ggagcagcct tacgtgttca tcaagaggtc cgatgcaagg acagcaccac acggacacgt 720
gatggtggag ctggtggccg agctggaggg catccagtat ggccgctctg gagagaccct 780
gggcgtgctg gtgccacacg tgggagagat cccagtggcc tatcggaagg tgctgctgag 840
aaagaacggc aataagggag caggaggaca ctcttacgga gcagacctga agagcttcga 900
tctgggcgac gagctgggca ccgatcctta tgaggacttt caggagaact ggaatacaaa 960
gcacagctcc ggcgtgaccc gggagctgat gagagagctg aacggcggcg cctacaccag 1020
atatgtggat aacaatttct gcggaccaga cggatacccc ctggagtgta tcaaggatct 1080
gctggccaga gcaggcaagg cctcctgcac cctgtctgag cagctggact tcatcgacac 1140
aaagcggggc gtgtattgct gtagagagca cgagcacgag atcgcctggt ataccgagcg 1200
gtccgagaag tcttacgagc tgcagacacc attcgagatc aagctggcca agaagttcga 1260
caccttcaac ggcgagtgtc caaacttcgt gtttcccctg aatagcatca tcaagaccat 1320
ccagcccaga gtggagaaga agaagctgga tggctttatg ggcaggatcc gcagcgtgta 1380
ccctgtggcc tccccaaacg agtgcaatca gatgtgcctg tccacactga tgaagtgcga 1440
tcactgtggc gagacctctt ggcagacagg cgacttcgtg aaggccacct gcgagttttg 1500
tggcaccgag aacctgacaa aggagggcgc caccacatgc ggctatctgc ctcagaatgc 1560
cgtggtgaag atctactgcc cagcctgtca caactccgaa gtgggaccag agcactctct 1620
ggccgagtac cacaatgagt ccggcctgaa gacaatcctg aggaagggag gaaggaccat 1680
cgccttcggc ggatgcgtgt tttcttatgt gggctgccac aacaagtgtg catactgggt 1740
gccaagggcc agcgccaata tcggctgtaa ccacaccgga gtggtgggag agggatccga 1800
gggcctgaac gataatctgc tggagatcct gcagaaggag aaggtgaaca tcaatatcgt 1860
gggcgacttc aagctgaacg aggagatcgc catcatcctg gcctccttct ctgccagcac 1920
atccgccttt gtggagaccg tgaagggcct ggactacaag gccttcaagc agatcgtgga 1980
gagctgcggc aacttcaagg tgaccaaggg caaggccaag aagggcgcct ggaacatcgg 2040
cgagcagaag agcatcctgt cccctctgta tgccttcgcc agcgaggcag caagggtggt 2100
gagatctatc tttagccgga ccctggagac agcccagaat tccgtgagag tgctgcagaa 2160
ggccgccatc accatcctgg atggcatctc ccagtactct ctgaggctga tcgatgccat 2220
gatgttcacc tccgacctgg ccacaaacaa tctggtggtc atggcctaca tcaccggcgg 2280
cgtggtgcag ctgacctctc agtggctgac aaacatcttt ggcaccgtgt atgagaagct 2340
gaagccagtg ctggattggc tggaggagaa gttcaaggag ggcgtggagt ttctgcgcga 2400
cggctgggag atcgtgaagt tcatcagcac ctgcgcatgt gagatcgtgg gaggacagat 2460
cgtgacctgt gccaaggaga tcaaggagtc cgtgcagaca ttctttaagc tggtgaacaa 2520
gttcctggcc ctgtgcgccg actctatcat catcggcggc gccaagctga aggccctgaa 2580
cctgggcgag acctttgtga cacacagcaa gggcctgtac aggaagtgcg tgaagtcccg 2640
cgaggagacc ggactgctga tgcccctgaa ggcacctaag gagatcatct tcctggaggg 2700
cgagaccctg cccacagagg tgctgacaga ggaggtggtg ctgaagaccg gcgacctgca 2760
gccactggag cagcccacca gcgaggcagt ggaggcacct ctggtgggca caccagtgtg 2820
catcaatggc ctgatgctgc tggagatcaa ggataccgag aagtactgtg ccctggcccc 2880
taacatgatg gtgacaaaca ataccttcac actgaagggc ggcgccccaa ccaaggtgac 2940
atttggcgac gataccgtga tcgaggtgca gggctacaag tctgtgaata tcacattcga 3000
gctggatgag agaatcgaca aggtgctgaa cgagaagtgc agcgcctata cagtggagct 3060
gggcaccgag gtgaacgagt ttgcctgcgt ggtggccgac gccgtgatca agaccctgca 3120
gccagtgtcc gagctgctga cacccctggg catcgatctg gacgagtggt ctatggccac 3180
ctactatctg ttcgacgaga gcggcgagtt taagctggcc tcccacatgt actgctcttt 3240
ctatccccct gatgaagacg aggaggaggg cgattgcgag gaggaggagt ttgagcccag 3300
cacacagtac gagtatggca ccgaggacga ttaccagggc aagccactgg agttcggagc 3360
cacctccgcc gccctgcagc cagaggagga gcaggaggag gattggctgg acgatgactc 3420
ccagcagacc gtgggccagc aggatggctc tgaggacaat cagaccacaa ccatccagac 3480
aatcgtggag gtgcagcctc agctggagat ggagctgacc ccagtggtgc agaccatcga 3540
ggtgaactct ttcagcggct atctgaagct gacagataac gtgtacatca agaacgccga 3600
cattgtggag gaggccaaga aggtgaagcc taccgtggtg gtgaacgccg ccaacgtgta 3660
cctgaagcac ggaggaggag tggcaggcgc cctgaacaag gccaccaaca atgccatgca 3720
ggtggagagc gatgactata tcgccacaaa tggacccctg aaggtcggag gaagctgcgt 3780
gctgtccgga cacaacctgg ccaagcactg tctgcacgtg gtgggcccta acgtgaataa 3840
gggcgaggac atccagctgc tgaagtccgc ctacgagaac ttcaatcagc acgaggtgct 3900
gctggcccct ctgctgagcg ccggcatctt tggcgccgat ccaatccact ccctgagggt 3960
gtgcgtggac accgtgcgca caaacgtgta cctggccgtg ttcgataaga acctgtacga 4020
caagctggtg tctagctttc tggagatgaa gagcgagaag caggtggagc agaagatcgc 4080
cgagatccct aaggaggagg tgaagccatt catcaccgag agcaagcctt ccgtggagca 4140
gaggaagcag gatgacaaga agatcaaggc ctgcgtggag gaggtgacaa ccacactgga 4200
ggagaccaag ttcctgacag agaacctgct gctgtacatc gatatcaacg gcaatctgca 4260
cccagacagc gccacactgg tgtccgatat cgacatcacc tttctgaaga aggatgcccc 4320
atatatcgtg ggcgacgtgg tgcaggaggg cgtgctgaca gccgtggtca tccccaccaa 4380
gaaggccggc ggcaccacag agatgctggc caaggccctg cgcaaggtgc ctaccgacaa 4440
ttacatcacc acatatccag gccagggcct gaacggctat accgtggagg aggccaagac 4500
cgtgctgaag aagtgcaaga gcgccttcta catcctgcct tctatcatca gcaatgagaa 4560
gcaggagatc ctgggcaccg tgtcctggaa cctgagggag atgctggccc acgccgagga 4620
gacacgcaag ctgatgcccg tgtgcgtgga gacaaaggcc atcgtgagca ccatccagcg 4680
gaagtataag ggcatcaaga tccaggaggg agtggtggac tacggagcaa gattctactt 4740
ttatacctct aagaccacag tggccagcct gatcaacaca ctgaatgatc tgaacgagac 4800
cctggtgaca atgcccctgg gctatgtgac ccacggcctg aatctggagg aggccgccag 4860
gtacatgcgc tccctgaagg tgccagcaac cgtgagcgtg agctctcctg acgccgtgac 4920
agcctacaac ggctatctga caagctcctc taagacccca gaggagcact tcatcgagac 4980
catctctctg gccggcagct ataaggattg gtcctactct ggccagtcca cacagctggg 5040
catcgagttt ctgaagaggg gcgacaagag cgtgtactat accagcaatc ccaccacatt 5100
ccacctggat ggcgaagtga tcaccttcga caacctgaag accctgctga gcctgcggga 5160
ggtgagaacc atcaaggtgt tcaccacagt ggataacatc aatctgcaca cacaggtggt 5220
ggacatgtcc atgacctatg gccagcagtt tggcccaaca tacctggatg gcgccgacgt 5280
gaccaagatc aagccccaca atagccacga gggcaagaca ttctacgtgc tgcctaatgc 5340
caccaacttt tccctgctga agcaggcagg cgacgtggag gagaacccag gaccagatga 5400
caccctgagg gtggaggcct tcgagtacta tcacaccaca gatcctagct ttctgggccg 5460
ctatatgtcc gccctgaatc acaccaagaa gtggaagtac ccacaggtga acggcctgac 5520
aagcatcaag tgggccgaca acaattgcta cctggccacc gccctgctga cactgcagca 5580
gatcgagctg aagttcaacc cacccgccct gcaggatgca tactataggg caagagcagg 5640
agaggcagcc aatttttgcg ccctgatcct ggcctattgt aacaagaccg tgggagagct 5700
gggcgatgtg cgggagacaa tgagctacct gttccagcac gccaatctgg actcctgcaa 5760
gagagtgctg aacgtggtgt gcaagacatg tggccagcag cagaccacac tgaagggcgt 5820
ggaggccgtg atgtatatgg gcaccctgag ctacgagcag tttaagaagg gcgtgcagat 5880
cccctgcaca tgtggcaagc aggccaccaa gtacctggtg cagcaggagt cccctttcgt 5940
gatgatgtct gcccctccag cccagtatga gctgaagcac ggcaccttta catgcgcctc 6000
tgagtacacc ggcaattatc agtgtggcca ctataagcac atcaccagca aggagacact 6060
gtactgcatc gatggcgccc tgctgaccaa gagctccgag tacaagggcc ccatcacaga 6120
cgtgttctat aaggagaatt cttacaccac aaccatcgcc accaacttta gcctgctgaa 6180
gcaggccggc gatgtggagg agaaccctgg accaaagccc gtgacctata agctggacgg 6240
cgtggtgtgc acagagatcg atcctaagct ggacaactac tacaagaagg ataactctta 6300
tttcaccgag cagcccatcg acctggtgcc taatcagcct tacccaaacg ccagcttcga 6360
taatttcaag ttcgtgtgcg acaatatcaa gtttgccgat gacctgaacc agctgaccgg 6420
atacaagaag ccagccagcc gggagctgaa ggtgacattc tttcctgatc tgaacggcga 6480
cgtggtggcc atcgactaca agcactatac accttccttc aagaagggcg ccaagctgct 6540
gcacaagcca atcgtgtggc acgtgaacaa tgccaccaat aaggccacat acaagccaaa 6600
cacctggtgc atcagatgtc tgtggtctac aaagcccgtg gagaccagca attcctttga 6660
tgtgctgaag agcgaggatg cccagggcat ggacaacctg gcctgcgagg acctgaagcc 6720
cgtgagcgag gaggtggtgg agaatcctac catccagaag gatgtgctgg agtgtaacgt 6780
gaagacaacc gaggtggtgg gcgacatcat cctgaagcct gccaacaatt ccctgaagat 6840
cacagaggaa gtgggccaca ccgatctgat ggccgcctac gtggacaatt ctagcctgac 6900
catcaagaag ccaaacgagc tgagcagggt gctgggcctg aagaccctgg ccacacacgg 6960
cctggccgca gtgaattccg tgccatggga caccatcgcc aattatgcca agcccttcct 7020
gaacaaggtg gtgagcacaa ccacaaacat cgtgacacgg tgcctgaacc gggtgtgcac 7080
caattacatg ccatatttct ttacactgct gctgcagctg tgcaccttta caaggtccac 7140
caattctcgc atcaaggcct ccatgcccac cacaatcgcc aagaacacag tgaagagcgt 7200
gggcaagttc tgcctggagg cctcctttaa ctacctgaag tcccccaatt tctctaagct 7260
gatcaacatc atcatctggt ttctgctgct gagcgtgtgc ctgggcagcc tgatctattc 7320
cacagccgcc ctgggcgtgc tgatgagcaa cctgggcatg ccttcctact gcaccggcta 7380
tcgggagggc tacctgaata gcaccaacgt gacaatcgcc acctactgta caggctctat 7440
cccatgcagc gtgtgcctgt ccggcctgga ttctctggac acctatcctt ccctggagac 7500
catccagatc acaatctcct ctttcaagtg ggacctgacc gcctttggcc tggtggcaga 7560
gtggttcctg gcctatatcc tgtttacaag attcttttac gtgctgggcc tggccgccat 7620
catgcagctg ttctttagct acttcgccgt gcactttatc tctaatagct ggctgatgtg 7680
gctgatcatc aacctggtgc agatggcccc catctccgcc atggtgagga tgtatatctt 7740
ctttgcctct ttctactacg tgtggaagag ctacgtgcac gtggtggacg gctgcaatag 7800
ctccacctgc atgatgtgct acaagaggaa ccgcgccaca cgcgtggagt gtaccacaat 7860
cgtgaatggc gtgcggagaa gcttctacgt gtatgccaac ggcggcaagg gcttttgcaa 7920
gctgcacaac tggaattgcg tgaactgtga tacattctgt gccggcagca cctttatctc 7980
cgatgaggtg gcaagggacc tgtccctgca gttcaagaga ccaatcaatc ccaccgatca 8040
gtctagctac atcgtggact ccgtgacagt gaagaacggc tctatccacc tgtatttcga 8100
taaggccggc cagaagacat acgagaggca ctccctgtct cactttgtga atctggacaa 8160
cctgcgcgcc aacaatacca agggcagcct gcccatcaac gtgatcgtgt tcgatggcaa 8220
gtccaagtgc gaggagtcct ctgccaagag cgcctccgtg tactatagcc agctgatgtg 8280
ccagcctatc ctgctgctgg accaggccct ggtgtccgat gtgggcgact ctgccgaggt 8340
ggcagtgaag atgtttgatg cctacgtgaa taccttcagc agcaccttca acgtgccaat 8400
ggagaagctg aagaccctgg tggcaacagc agaggcagag ctggccaaga acgtgtccct 8460
ggacaatgtg ctgtctacct tcatcagcgc cgcccgccag ggctttgtgg attctgacgt 8520
ggagacaaag gatgtggtgg agtgcctgaa gctgagccac cagtccgata tcgaggtgac 8580
cggcgacagc tgtaacaatt atatgctgac ctacaataag gtggagaaca tgacaccccg 8640
ggatctgggc gcctgcatcg actgttctgc cagacacatc aatgcccagg tggccaagag 8700
ccacaatatc gccctgatct ggaacgtgaa ggacttcatg tctctgagcg agcagctgag 8760
gaagcagatc cgctccgccg ccaagaagaa caatctgccc ttcaagctga cctgcgccac 8820
cacaaggcag gtggtgaacg tggtcaccac aaagatcgcc ctgaagggcg gcaagatcgt 8880
gaacaattgg ctgaagcagc tgatcaaggt gaccctggtg ttcctgtttg tggccgccat 8940
cttctacctg atcacccccg tgcacgtgat gtctaagcac acagattttt ctagcgagat 9000
catcggctat aaggccatcg acggaggagt gaccagggat atcgccagca ccgacacatg 9060
cttcgccaat aagcacgccg atttcgacac ctggtttagc cagaggggcg gctcctacac 9120
aaacgacaag gcctgtccac tgatcgcagc cgtgatcacc agggaagtgg gattcgtggt 9180
gcctggactg ccaggaacaa tcctgaggac cacaaatggc gacttcctgc actttctgcc 9240
tcgcgtgttt tccgccgtgg gcaacatctg ctatacccca tctaagctga tcgagtacac 9300
cgatttcgcc acatccgcct gcgtgctggc cgcagagtgt accatcttta aggatgcctc 9360
tggcaagccc gtgccttact gttatgacac aaatgtgctg gagggctctg tggcctatga 9420
gagcctgcgg ccagatacca gatacgtgct gatggacggc agcatcatcc agttccccaa 9480
cacatatctg gagggctctg tgcgggtggt gaccacattt gacagcgagt actgccggca 9540
cggcacctgt gagagatctg aggccggcgt gtgcgtgtcc acatctggca ggtgggtgct 9600
gaacaatgat tactatcgca gcctgcctgg cgtgttctgt ggcgtggacg ccgtgaatct 9660
gctgaccaac atgtttacac ctctgatcca gccaatcggc gccctggata tcagcgcctc 9720
catcgtggca ggaggaatcg tggcaatcgt ggtgacatgc ctggcctact atttcatgcg 9780
gttccggagg gccttcggcg agtactctca cgtggtggcc tttaataccc tgctgttcct 9840
gatgagcttc accgtgctgt gcctgacccc cgtgtatagc ttcctgcctg gcgtgtactc 9900
cgtgatctac ctgtatctga ccttctacct gacaaacgac gtgagctttc tggcccacat 9960
ccagtggatg gtcatgttca cccccctggt gcctttttgg atcacaatcg cctatatcat 10020
ctgcatctcc accaagcact tctattggtt cttttctaat tacctgaagc ggagagtggt 10080
gtttaacggc gtgtctttca gcacctttga ggaggccgcc ctgtgcacat tcctgctgaa 10140
caaggagatg tacctgaagc tgcggtccga cgtgctgctg ccactgaccc agtacaatag 10200
atatctggcc ctgtataaca agtacaagta tttctctggc gccatggata ccacaagcta 10260
cagagaggca gcatgctgtc acctggcaaa ggccctgaat gatttttcca actctggcag 10320
cgacgtgctg taccagcccc ctcagacctc tatcacaagc gccgtgctgc agtaactagc 10380
ataacccctt ggggcctcta aacgggtctt gaggggtttt ttgtctaga 10429
<210> 3
<211> 4012
<212> DNA
<213> Artificial sequence
<400> 3
gctagcgagg gcccggaaac ctggccctgt cttcttgacg agcattccta ggggtctttc 60
ccctctcgcc aaaggaatgc aaggtctgtt gaatgtcgtg aaggaagcag ttcctctgga 120
agcttcttga agacaaacaa cgtctgtagc gaccctttgc aggcagcgga accccccacc 180
tggcgacagg tgcctctgcg gccaaaagcc acgtgtataa gatacacctg caaaggcggc 240
acaaccccag tgccacgttg tgagttggat agttgtggaa agagtcaaat ggctctcctc 300
aagcgtattc aacaaggggc tgaaggatgc ccagaaggta ccccattgta tgggatctga 360
tctggggcct cggtgcacat gctttacatg tgtttagtcg aggttaaaaa aacgtctagg 420
ccccccgaac cacggggacg tggttttcct ttgaaaaaca cgatgataaa tgagcggctt 480
tcggaagatg gcattcccat ccggcaaggt ggagggatgc atggtgcagg tgacatgtgg 540
caccacaacc ctgaatggcc tgtggctgga cgatgtggtg tattgcccta gacacgtgat 600
ctgtaccagc gaggacatgc tgaacccaaa ttacgaggat ctgctgatca ggaagtccaa 660
ccacaatttc ctggtgcagg caggaaacgt gcagctgcgc gtgatcggcc acagcatgca 720
gaattgcgtg ctgaagctga aggtggacac agccaaccca aagaccccca agtacaagtt 780
tgtgaggatc cagcctggcc agacattctc cgtgctggcc tgctataacg gctctcccag 840
cggcgtgtac cagtgtgcca tgcgccctaa ctttaccatc aagggctctt tcctgaatgg 900
cagctgcggc tccgtgggct ttaacatcga ctatgattgc gtgagcttct gttacatgca 960
ccacatggag ctgccaacag gagtgcacgc aggaaccgac ctggagggaa acttctacgg 1020
ccccttcgtg gacaggcaga ccgcacaggc agcaggcaca gatacaacca tcaccgtgaa 1080
cgtgctggcc tggctgtacg ccgccgtgat caacggcgac cggtggtttc tgaatagatt 1140
cacaaccaca ctgaacgatt tcaatctggt ggccatgaag tacaactatg agccactgac 1200
acaggaccac gtggatatcc tgggaccact gagcgcccag accggaatcg ccgtgctgga 1260
catgtgcgcc tccctgaagg agctgctgca gaacggcatg aatggaagga caatcctggg 1320
aagcgccctg ctggaggacg agtttacccc attcgatgtg gtgagacagt gttccggcgt 1380
gacatttcag gccaccaatt tctctctgct gaagcaggca ggcgatgtgg aggagaaccc 1440
tggaccatcc gccgtgaagc gcacaatcaa gggcacccac cactggctgc tgctgacaat 1500
cctgacctct ctgctggtgc tggtgcagtc tacccagtgg agcctgttct ttttcctgta 1560
tgagaatgcc tttctgccct tcgccatggg catcatcgcc atgtccgcct ttgccatgat 1620
gttcgtgaag cacaagcacg cctttctgtg cctgttcctg ctgccatccc tggccaccgt 1680
ggcctacttc aacatggtgt atatgcctgc ctcttgggtc atgaggatca tgacatggct 1740
ggacatggtg gatacctccc tgtctggctt taagctgaag gactgcgtga tgtatgccag 1800
cgccgtggtg ctgctgatcc tgatgacagc aaggaccgtg tacgacgatg gagcaaggag 1860
agtgtggaca ctgatgaatg tgctgaccct ggtgtacaag gtgtactatg gcaacgccct 1920
ggatcaggcc atctccatgt gggccctgat catctctgtg accagcaatt attccggcgt 1980
ggtgaccaca gtgatgtttc tggcccgggg catcgtgttc atgtgcgtgg agtactgtcc 2040
tatctttttc atcacaggca acaccctgca gtgcatcatg ctggtgtact gttttctggg 2100
ctatttctgc acctgttact ttggcctgtt ctgcctgctg aataggtatt ttcgcctgac 2160
actgggcgtg tacgactatc tggtgtctac ccaggagttc agatacatga acagccaggg 2220
cctgctgccc cctaagaact ccatcgatgc cttcaagctg aatatcaagc tgctgggcgt 2280
gggcggcaag ccatgcatca aggtggccac agtgcagtct aagatgagcg acgtgaagtg 2340
taccagcgtg gtgctgctgt ccgtgctgca gcagctgagg gtggagagct cctctaagct 2400
gtgggcccag tgcgtgcagc tgcacaacga catcctgctg gccaaggata ccacagaggc 2460
cttcgagaag atggtgtccc tgctgtctgt gctgctgagc atgcagggcg ccgtggacat 2520
caataagctg tgcgaggaga tgctggataa ccgcgccaca ctgcaggcca tcgcctctga 2580
gtttagctcc ctgccaagct atgcagcctt cgccaccgca caggaggcat acgagcaggc 2640
cgtggccaat ggcgactccg aggtggtgct gaagaagctg aagaagagcc tgaacgtggc 2700
caagtccgag ttcgaccggg atgccgccat gcagagaaag ctggagaaga tggccgacca 2760
ggccatgaca cagatgtata agcaggccag gtctgaggat aagcgcgcca aggtgaccag 2820
cgccatgcag acaatgctgt ttaccatgct gcggaagctg gacaatgatg ccctgaacaa 2880
tatcatcaac aatgccagag acggctgcgt gcccctgaac atcatccctc tgaccacagc 2940
cgccaagctg atggtggtca tccctgacta caacacatat aagaatacct gtgatggcac 3000
cacattcaca tacgcctctg ccctgtggga gatccagcag gtggtggacg ccgatagcaa 3060
gatcgtgcag ctgagcgaga tctccatgga taactcccca aatctggcat ggccactgat 3120
cgtgaccgcc ctgagggcca atagcgccgt gaagctgcag aacaatgagc tgtccccagt 3180
ggccctgagg cagatgtctt gcgcagcagg aaccacacag acagcctgta ccgacgataa 3240
cgccctggcc tactataata ccacaaaggg aggccggttt gtgctggccc tgctgtctga 3300
cctgcaggat ctgaagtggg ccagattccc taagagcgac ggcaccggca caatctacac 3360
cgagctggag ccaccctgcc ggtttgtgac cgatacacct aagggcccaa aggtgaagta 3420
cctgtatttc atcaagggcc tgaacaatct gaacagggga atggtgctgg gatctctggc 3480
cgcaaccgtg cgcctgcagg caggaaacgc cacagaggtg cccgccaatt ccaccgtgct 3540
gtctttttgt gccttcgccg tggacgcagc aaaggcatac aaggattatc tggcctccgg 3600
cggccagcct atcaccaatt gcgtgaagat gctgtgcacc cacacaggaa ccggacaggc 3660
catcacagtg accccagagg ccaacatgga ccaggagtct tttggcggcg ccagctgctg 3720
tctgtattgc cggtgtcaca tcgaccaccc caatcctaag ggcttctgcg atctgaaggg 3780
caagtacgtg cagatcccta ccacatgtgc caatgatcca gtgggcttta ccctgaagaa 3840
cacagtgtgc accgtgtgcg gcatgtggaa gggctacggc tgcagctgtg accagctgag 3900
agagcccatg ctgcagtccg ccgatgccca gtcttttctg aacggcttcg ccgtgtaact 3960
agcataaccc cttggggcct ctaaacgggt cttgaggggt tttttgtcta ga 4012
<210> 4
<211> 8641
<212> DNA
<213> Artificial sequence
<400> 4
gctagcgagg gcccggaaac ctggccctgt cttcttgacg agcattccta ggggtctttc 60
ccctctcgcc aaaggaatgc aaggtctgtt gaatgtcgtg aaggaagcag ttcctctgga 120
agcttcttga agacaaacaa cgtctgtagc gaccctttgc aggcagcgga accccccacc 180
tggcgacagg tgcctctgcg gccaaaagcc acgtgtataa gatacacctg caaaggcggc 240
acaaccccag tgccacgttg tgagttggat agttgtggaa agagtcaaat ggctctcctc 300
aagcgtattc aacaaggggc tgaaggatgc ccagaaggta ccccattgta tgggatctga 360
tctggggcct cggtgcacat gctttacatg tgtttagtcg aggttaaaaa aacgtctagg 420
ccccccgaac cacggggacg tggttttcct ttgaaaaaca cgatgataaa tgtcagcaga 480
tgcacaatca tttcttaaca gagtgtgcgg agtgtcagca gcaagactta caccttgcgg 540
aacaggaaca tcaacagatg tagtttatag ggccttcgat atctacaacg ataaagtggc 600
aggatttgca aagttcttaa agaccaattg ctgcagattt caagagaagg acgaggatga 660
taaccttatc gattcatact ttgtggtgaa gaggcataca ttcagcaatt accaacacga 720
agaaacaatc tacaaccttc ttaaagattg ccctgcagtg gcaaagcatg acttcttcaa 780
gttcagaatc gatggagata tggtgcctca catctcaaga caaagactta caaagtatac 840
gatggcagat ctcgtttatg cgttgcgcca tttcgacgag ggtaattgtg acaccctgaa 900
ggagatcctg gtcacgtata attgctgcga tgatgattac tttaacaaga aggactggta 960
tgatttcgta gagaatcctg acattcttag agtgtacgca aaccttggag aaagagtgag 1020
acaagcactc ctaaagacag ttcaattctg cgacgcaatg agaaacgcag gaatcgtggg 1080
agtgcttaca cttgataacc aagatcttaa cggaaactgg tatgactttg gcgactttat 1140
acagacaaca cctggatcag gagtgcctgt ggtggattca tattatagcc tgctgatgcc 1200
tatccttaca cttacaagag cacttacagc agaatcacat gtggataccg acttgaccaa 1260
accctatatt aaatgggatc tgctgaaata tgactttaca gaagaacgac ttaaactctt 1320
cgacagatac tttaaatact gggatcaaac ataccaccct aactgcgtga actgccttga 1380
tgatagatgc atccttcact gcgcaaactt taacgtgctg ttctcgaccg tgtttcctcc 1440
tacatcattt ggacctcttg tgagaaagat ctttgtggac ggagtacctt tcgtcgtatc 1500
aacaggatac cactttagag aacttggagt agtgcataat caagatgtga acctacattc 1560
tagccgatta tcatttaaag aacttctggt ttatgccgcg gaccctgcaa tgcacgcagc 1620
aagtggcaat ttattacttg acaaacggac aacctgtttc tcggttgccg cacttacaaa 1680
caatgtagct ttccagaccg taaagccagg gaatttcaac aaagatttct atgacttcgc 1740
cgtatcaaag ggattcttca aggagggatc atcagtggaa cttaaacact tcttcttcgc 1800
ccaggatgga aacgcagcaa tctcagatta cgattactac agatacaacc ttcctacaat 1860
gtgcgatatc agacaacttc tcttcgtagt tgaagtggtg gataaatact ttgattgcta 1920
cgatggagga tgcatcaacg caaaccaagt gatcgtgaac aacttggata aatccgctgg 1980
attcccgttt aataagtggg gtaaagcccg cctttactac gattcaatgt catacgaaga 2040
tcaagatgca ttattcgctt atacaaagag gaatgtgatc cctacaatca cacaaatgaa 2100
ccttaaatac gcaatctcag caaagaatcg agcaagaaca gtggcaggag tgtcaatctg 2160
ctcaacaatg acaaacagac aatttcacca gaagctcctg aaatcaatcg cagcaacaag 2220
aggagcaaca gtggtgatcg gaacatcaaa gttctatgga ggttggcaca acatgctcaa 2280
gaccgtgtat agcgatgttg agaatccgca tctcatggga tgggattacc ctaaatgcga 2340
tagagctatg cccaatatgc tgagaatcat ggcatcactt gtgcttgcaa gaaagcatac 2400
cacatgctgc tcactttcac acagattcta tcgacttgca aacgaatgcg cacaggtcct 2460
ctccgagatg gtgatgtgcg gcgggagctt gtatgtgaaa ccaggtggaa catcatcagg 2520
agatgcaaca acagcatacg caaactcagt gtttaacatc tgccaagcag tgacagctaa 2580
tgtaaacgct ctcttgagca ctgacggaaa caagatagcc gataaatacg tgcgtaatct 2640
gcagcatcga ctttacgaat gcctttacag aaacagagat gtagacacgg actttgtaaa 2700
tgaattctat gcttacctta gaaagcattt ctccatgatg atactgagtg acgatgctgt 2760
tgtatgtttc aactcaacat acgcatcaca aggacttgtg gcatcaatca agaatttcaa 2820
atcagtgctt tactaccaga ataatgtgtt tatgtcagaa gcaaagtgtt ggacagaaac 2880
tgacctcact aagggccctc acgagttctg tagccaacac acaatgcttg tgaaacaagg 2940
agatgactat gtttatctcc cataccctga tccttcaaga atcttgggtg cagggtgttt 3000
cgtggatgat atcgtgaaga ctgacggaac acttatgatc gaaagatttg tgtcacttgc 3060
aatcgatgca taccctctta caaagcatcc gaaccaagaa tacgcagatg tgtttcacct 3120
ttaccttcaa tacatcagaa agttgcatga tgaacttaca ggacacatgc ttgatatgta 3180
ctcagtgatg cttacaaacg ataacacatc aagatactgg gaacctgaat tctatgaggc 3240
aatgtacaca cctcacacag tgcttcaagc agtgggagca tgcgtgcttt gcaactcaca 3300
aacatcactt agatgcggag catgcatcag aagacctttc ctgtgttgca aatgctgcta 3360
cgatcacgtg atctcaacat cacacaaact tgtgctttca gtgaaccctt acgtgtgcaa 3420
cgcaccaggc tgtgacgtaa ctgacgttac gcagctctat cttggaggaa tgtcatacta 3480
ctgcaaatca cacaaacctc ctatctcatt tcctctttgc gcaaacggac aagtgtttgg 3540
actttacaag aatacttgcg tgggatcaga taacgtgaca gatttcaatg ctatcgcaac 3600
atgcgattgg acaaacgcag gagattacat ccttgcaaac acatgcacag agcgtctgaa 3660
gttgtttgcg gccgaaacac ttaaagcaac agaagaaaca tttaaacttt catacggaat 3720
cgcaacagtg agagaggtcc tatcggacag ggaactccac ctttcatggg aagtgggcaa 3780
accacgcccg ccgcttaaca gaaactacgt gtttacagga tacagagtga caaagaattc 3840
taaggtacag atcggagaat acacatttga gaagggcgac tacggagacg ccgtggtgta 3900
cagagggacg actacgtata aacttaacgt gggagattac tttgtgctta catcacacac 3960
agtgatgcct ctttcagcac ctacacttgt gcctcaagag cattatgtcc gaataacggg 4020
tctctatccg acacttaaca tctcagatga attctcgagt aacgtggcaa actaccagaa 4080
agtgggtatg cagaaatact ccaccttaca gggacctcct ggtacaggaa agtctcattt 4140
cgcgataggt ctagctctct attacccttc agcaagaatc gtgtacacag catgctcaca 4200
cgcagcagtg gatgcacttt gcgagaaggc gctgaaatac cttcctatcg ataaatgctc 4260
aagaatcatc cctgcaagag caagagtgga atgctttgat aaatttaaag tgaactcaac 4320
acttgaacaa tacgtgttct gtactgtaaa tgctctgcct gaaactaccg cggatatcgt 4380
ggtgttcgac gagatatcca tggcaacaaa ctacgaccta tcggtcgtaa acgcgcggct 4440
aagagcaaag cattatgtgt acatcggaga tcctgcacaa cttcctgcac ctagaacatt 4500
actaactaaa gggacgctcg aacctgaata ctttaacagt gtttgtcgcc taatgaagac 4560
gatcgggccg gacatgtttc ttggaacatg cagaagatgc cctgcagaaa tcgtggatac 4620
agtgtcagca cttgtgtacg ataacaaact taaagcacac aaagacaagt cggctcagtg 4680
tttcaagatg ttttacaaag gagtgatcac acacgatgtg tcatcagcaa tcaacagacc 4740
tcaaatcgga gtggtgagag aatttcttac aagaaaccct gcatggagaa aggcggtctt 4800
cataagtcct tacaactcac agaatgccgt ggcatcaaag atactcgggc ttcctacaca 4860
aacagtggat tcatcacaag gatcagaata cgattacgtg atctttacac aaacaacaga 4920
aacagcacac tcatgcaacg tgaacagatt taacgtggca atcacaagag caaaggtagg 4980
gatcctctgt atcatgtcag atagagatct ttacgataaa cttcaattta catcacttga 5040
aatccctaga agaaacgtgg cgactctgca ggctgagaac gtgacaggat tgttcaagga 5100
ctgctcaaag gtaattacgg gtttacatcc gacacaagca cctacacacc tttcagtgga 5160
tacaaagttc aagactgaag gactttgcgt ggatatccct ggaatcccta aagatatgac 5220
atacagaaga cttatctcaa tgatgggatt taagatgaat taccaagtga acggataccc 5280
taacatgttt atcacaagag aagaagcaat cagacacgtg agagcatgga taggcttcga 5340
cgtcgaggga tgccacgcaa caagagaagc agtgggaaca aaccttcctc ttcaacttgg 5400
attctccact ggagtgaacc ttgtggcagt gcctacagga tacgtggata cacctaacaa 5460
cacagatttc tcgcgagtgt cagcaaagcc accacctgga gatcaattta aacaccttat 5520
ccctcttatg tacaaaggac ttccttggaa cgtggtgaga atcaagatag tccaaatgct 5580
atccgatacc ttaaagaatc ttagtgaccg tgtcgtattt gtgctttggg cacacggatt 5640
tgaacttaca tcaatgaaat actttgtgaa gatcggtccc gagcgtacat gctgcctttg 5700
cgatagaaga gctacgtgtt tcagtaccgc ttcagataca tacgcatgct ggcaccactc 5760
aataggcttc gattacgttt ataatccgtt catgatagat gtgcaacaat ggggattcac 5820
gggcaatctg cagagcaacc acgatcttta ctgccaagtg cacggaaacg cacacgtggc 5880
atcatgcgat gcaatcatga caagatgcct tgcagtgcac gaatgctttg tgaagcgggt 5940
cgattggaca atcgaatacc ctatcatcgg agatgaactt aagataaatg cagcatgcag 6000
aaaggtccag cacatggtgg tgaaagcagc acttcttgca gataaatttc ctgtgcttca 6060
cgatatcgga aaccctaaag caatcaaatg cgtgcctcaa gcagatgtgg aatggaaatt 6120
ctatgacgca caaccttgct cagataaagc atacaagata gaggaactat tctatagtta 6180
cgcaacacac tcagataaat ttacagatgg agtgtgcctg ttctggaatt gcaacgtgga 6240
tagataccct gcaaactcaa tcgtgtgcag atttgataca agagtgcttt caaaccttaa 6300
ccttccaggt tgtgacggcg gcagtctata tgttaataag cacgcatttc acacacctgc 6360
attcgataag tccgcattcg tcaatttaaa gcagctacct ttcttctatt attcagattc 6420
accttgcgaa tcacacggaa agcaggttgt cagtgacatc gattacgtgc ctcttaaatc 6480
agcaacatgt attaccaggt gtaatcttgg aggagccgtc tgtcgacatc atgcaaacga 6540
atacagactt taccttgatg catacaacat gatgatctcc gccgggttct ccctatgggt 6600
gtacaaacaa tttgatacat acaacctttg gaacacattt acaagacttc aatcacttga 6660
gaacgttgcg ttcaatgtag tcaataaggg acacttcgac ggtcaacagg gtgaggttcc 6720
tgtgtcaatc atcaacaata ccgtttatac taaagttgac ggcgtggatg tggaactctt 6780
cgagaataag actacgcttc ctgtgaatgt tgccttcgag ttgtgggcaa agcgcaatat 6840
caaacctgtg cctgaagtga agatactcaa taaccttgga gtggatatcg cagcaaacac 6900
agtgatctgg gattacaaga gggacgcacc tgcacacatc tcaacaatcg gagtgtgctc 6960
aatgacagat atcgcaaaga agccgactga aacaatctgc gcacctctta ctgtattctt 7020
cgacggaaga gtggatggac aagtggattt attccgaaat gcaagaaacg gagtgcttat 7080
cacagaagga tcagtgaaag gacttcaacc ttcagtggga cctaaacaag catcacttaa 7140
cggagtgact ctgataggcg aggccgtgaa gactcagttt aactactaca agaaagtaga 7200
cggtgtcgtc cagcagctgc ccgagaccta tttcacacaa tcacggaatc tgcaggagtt 7260
caaacctaga tcacaaatgg aaatcgattt cctggagctt gcaatggatg aatttatcga 7320
aagatacaaa cttgaaggat acgcatttga acacatcgtg tacggagatt tcagtcattc 7380
acaacttgga ggacttcacc ttcttattgg cctagccaaa cgtttcaaag aatcaccttt 7440
cgagctcgaa gatttcattc caatggattc aacagtgaag aattatttca ttactgacgc 7500
ccagacggga tcatcaaagt gtgtatgctc agtgatcgat ctactactag acgatttcgt 7560
tgaaattatt aaatcacaag acttgagtgt agttagtaag gttgtgaagg tcacaatcga 7620
ttacacagaa atctcattta tgctttggtg caaagatgga cacgtggaaa cattctatcc 7680
caaacttcaa tcatcacaag catggcaacc tggagtggcc atgccgaatt tgtataagat 7740
gcagagaatg cttcttgaga agtgtgacct tcagaattat ggagattcag caacacttcc 7800
taaaggaatc atgatgaacg tggcaaagta tactcaactt tgccaatacc ttaacacact 7860
tacacttgca gtgccttaca acatgagagt gatccacttc ggtgcagggt cggacaaagg 7920
agtggcacct ggtactgctg tccttagaca atggcttcct acaggaacac ttcttgtgga 7980
ttcagatctt aacgatttcg tctccgatgc agattcaacc ctcattggtg actgtgcaac 8040
agtgcacaca gcaaacaagt gggacttaat aatatcagat atgtacgatc ctaagactaa 8100
gaatgtaacg aaagagaatg actcaaagga aggtttcttc acctatatct gcggatttat 8160
ccaacagaag ttagctcttg gaggatcagt ggcaatcaag attacggaac actcatggaa 8220
cgcagatctt tacaaactta tgggacactt tgcatggtgg accgcgttcg ttacaaacgt 8280
aaacgcgtcg tcctcagaag catttcttat cggatgcaac taccttggga aaccaagaga 8340
gcagatcgat ggatacgtga tgcacgcaaa ctacatcttc tggaggaaca caaaccctat 8400
ccaactttca tcatactcac tcttcgacat gtcaaagttc ccgcttaaac ttagagggac 8460
tgccgtaatg tcgcttaaag aaggacaaat caacgatatg atactcagcc tcctaagtaa 8520
agggaggctt atcatcagag agaataatag agtggtgatc tcatcagatg tgcttgtgaa 8580
caactaacta gcataacccc ttggggcctc taaacgggtc ttgaggggtt ttttgtctag 8640
a 8641
Claims (3)
1. Application of roxacitinib in preparing medicine for treating SARS-CoV-2 infection is provided.
2. Application of roxcetitinib in preparing medicine for treating SARS-CoV-2 inflammation is provided.
3. Application of roxacitinib in preparing SARS-CoV-2 RNA replication inhibitor is provided.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010917293.5A CN111991559B (en) | 2020-09-03 | 2020-09-03 | Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010917293.5A CN111991559B (en) | 2020-09-03 | 2020-09-03 | Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111991559A CN111991559A (en) | 2020-11-27 |
| CN111991559B true CN111991559B (en) | 2022-03-22 |
Family
ID=73465423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010917293.5A Active CN111991559B (en) | 2020-09-03 | 2020-09-03 | Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111991559B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112029781B (en) * | 2020-08-14 | 2023-01-03 | 中山大学 | Novel coronavirus SARS-CoV-2 safety replicon system and application thereof |
| CN112618547B (en) * | 2020-12-23 | 2022-02-11 | 中国医学科学院医药生物技术研究所 | Application of quinoline compound in preparation of anti-coronavirus preparation |
| CN114377010B (en) * | 2022-01-26 | 2023-04-07 | 中山大学 | Application of PKC kinase inhibitor in preparation of medicine for preventing and treating diseases related to novel coronavirus infection |
| CN115025094A (en) * | 2022-03-28 | 2022-09-09 | 中国人民解放军海军军医大学 | Application of masitinib in preparation of drugs for resisting infection of tick-borne encephalitis virus West Nile virus yellow fever virus and chikungunya virus |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014043442A1 (en) * | 2012-09-14 | 2014-03-20 | Children's Medical Center Corporation | Inhibition of viral infection-triggered asthma with c-kit inhibitor |
| WO2014079709A1 (en) * | 2012-11-23 | 2014-05-30 | Ab Science | Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections |
| CN111386128A (en) * | 2017-11-06 | 2020-07-07 | 奥瑞基尼探索技术有限公司 | Combination therapy for immunomodulation |
| CN111450097A (en) * | 2020-02-27 | 2020-07-28 | 中国人民解放军军事科学院军事医学研究院 | Application of Abl tyrosine kinase inhibitor in preparation of medicine for treating diseases caused by coronavirus |
| CN111558044A (en) * | 2020-06-01 | 2020-08-21 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Pharmaceutical composition containing sunitinib, and preparation and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200237773A1 (en) * | 2017-08-03 | 2020-07-30 | Novartis Ag | Therapeutic combination of a third-generation egfr tyrosine kinase inhibitor and a raf inhibitor |
-
2020
- 2020-09-03 CN CN202010917293.5A patent/CN111991559B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014043442A1 (en) * | 2012-09-14 | 2014-03-20 | Children's Medical Center Corporation | Inhibition of viral infection-triggered asthma with c-kit inhibitor |
| WO2014079709A1 (en) * | 2012-11-23 | 2014-05-30 | Ab Science | Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections |
| CN111386128A (en) * | 2017-11-06 | 2020-07-07 | 奥瑞基尼探索技术有限公司 | Combination therapy for immunomodulation |
| CN111450097A (en) * | 2020-02-27 | 2020-07-28 | 中国人民解放军军事科学院军事医学研究院 | Application of Abl tyrosine kinase inhibitor in preparation of medicine for treating diseases caused by coronavirus |
| CN111558044A (en) * | 2020-06-01 | 2020-08-21 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Pharmaceutical composition containing sunitinib, and preparation and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| "COVID-19 in lung cancer patients receiving ALK/ROS1 inhibitors;Leonetti，等;《European Journal of Cancer》;20200423;第122页右栏第1段、第122页右栏第2段-第123页左栏第3段、第123页左栏第2段、图1 * |
| Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2 in vitro;Nir Drayman，等;《bioRxiv》;20200901;摘要、图2、第7页第2段 * |
| Engineering a Reliable and Convenient SARS-CoV-2 Replicon System for Analysis of Viral RNA Synthesis and Screening of Antiviral Inhibitors;Yuewen Luo，等;《mBio》;20210119 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111991559A (en) | 2020-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111991559B (en) | Application of receptor tyrosine kinase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection | |
| CN112076182B (en) | Application of DNA topoisomerase inhibitor in preparation of medicine for preventing and/or treating novel coronavirus infection | |
| CN112029781B (en) | Novel coronavirus SARS-CoV-2 safety replicon system and application thereof | |
| KR101647843B1 (en) | Reoviruses having modified sequences | |
| CN113249380B (en) | Antisense oligonucleotide targeting COVID-19 novel coronavirus, NATAC chimeric molecule and application thereof | |
| US20230151367A1 (en) | Therapeutic interfering particles for corona virus | |
| CN109276580B (en) | A virus for treating tumor | |
| CN112567046A (en) | Messenger RNA cap substituted by two RNA sequences introduced at the 5' end of messenger RNA | |
| Varmus et al. | Synthesis, structure, and integration of the DNA of RNA tumor viruses | |
| CN112516131A (en) | Application of salvianolic acid B or its pharmaceutically acceptable salt in preparing anti-SARS-CoV-2 medicine | |
| CN109568350B (en) | Coxsackie virus for treating tumors | |
| Morange | The discovery of cellular oncogenes | |
| CN112359115B (en) | miR-517a-3p related to cisplatin resistance of tumor cells and application thereof | |
| CN101658522B (en) | Application of tacrine short-chain dimer in preparation of medicament for treating neurodegenerative diseases | |
| WO2018101498A1 (en) | Gene therapy vector system and prodrug genes | |
| CN112996802A (en) | Method for preparing anti-tumor arenavirus and arenavirus mutant | |
| CN116724110A (en) | Recombinant oncolytic virus and construction method and application thereof | |
| CN113069462A (en) | New use of cynanchum otophyllum saponin M1 | |
| CN114246853B (en) | Use of isoferulic acid in preparation of products for preventing and treating coronavirus infection | |
| CN115350181B (en) | Application of small molecular compound in preparation of antiviral infection medicines | |
| CN114042160B (en) | CTD-2256P15.2 and application of encoded micro-peptide thereof as target in development of tumor treatment drugs | |
| CN112410430B (en) | Marker related to cisplatin resistance of tumor cells and application thereof | |
| CN115181756B (en) | Recombinant lentiviral vector, recombinant lentiviral plasmid, cell model and related applications | |
| CN114246858A (en) | Application of artemisinin compound in treatment and prevention of coronavirus infection | |
| Williams et al. | TRAFfic signals: High-throughput CAR discovery in NK cells reveals novel TRAF-binding endodomains that drive enhanced persistence and cytotoxicity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |