CN115414364A - Anti-neocoronavirus drug taking RNA G-quadruplex as target spot and screening method thereof - Google Patents
Anti-neocoronavirus drug taking RNA G-quadruplex as target spot and screening method thereof Download PDFInfo
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- CN115414364A CN115414364A CN202211163372.7A CN202211163372A CN115414364A CN 115414364 A CN115414364 A CN 115414364A CN 202211163372 A CN202211163372 A CN 202211163372A CN 115414364 A CN115414364 A CN 115414364A
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Abstract
The invention provides a new crown virus resisting medicine taking RNA G-quadruplex as a target spot and a screening method thereof, the medicine comprises topotecan or berbamine, and the screening method specifically comprises the following steps: screening to obtain a drug compound with stable G-quadruplexes, and screening out drugs which are approved to enter clinic; screening out the medicine which is stably combined with the G-quadruplex and eliminates the toxicity of the cardiopulmonary function by utilizing a computer molecular Docking technology, and screening out the compound which is ranked at the first two positions by Docking, namely the anti-new coronavirus medicine. The clinical medicine obtained by the screening method can inhibit SARS-CoV-2 infection by down-regulating SARS-CoV-2 key host gene expression, and the medicine obtained by the screening method can be directly applied to human body, thus effectively solving the problem that the anti-neocoronaria medicine developed at present can be applied to human body by clinical test.
Description
Technical Field
The invention belongs to the technical field of screening of new coronavirus medicines, and particularly relates to a new coronavirus resisting medicine taking an RNA G-quadruplex as a target spot and a screening method thereof.
Background
The world public health safety is seriously jeopardized by the novel Coronavirus pneumonia (Corona Virus Disease 2019, COVID-19) caused by the novel Coronavirus (Severe acid Respiratory Syndrome Coronavir 2, SARS-CoV-2). Although various vaccines and antiviral drugs are approved to be marketed at present, the frequent virus strain mutation promotes SARS-CoV-2 to escape from infection before or the immunity of the organism caused by vaccination, so that the resistance effect of the vaccine to SARS-CoV-2 is reduced, and SARS-CoV-2 has high infectivity and pathogenicity. In addition, a recent global large-scale clinical trial showed that Redesivir, hydroxychloroquine, ritonavir, interferon, etc. were ineffective or minimally effective in COVID-19. Therefore, in order to solve the problems that the SARS-CoV-2 mutant strain has immune escape and various clinical drugs have no obvious curative effect, the search for a broader-spectrum anti-new coronavirus therapy is still urgent.
SARS-CoV-2 is a positive single-stranded RNA virus with envelope, as an organism without cell structure, and must mobilize host factors to complete the life cycle of virus entry, uncoating, replication, maturation, etc. The process of SARS-CoV-2 entering host cells is quite complex, and relates to the regulation of a plurality of host factors, and at present, the activation and mediation mainly depend on Angiotensin Converting Enzyme 2 (ACE 2), transmembrane Serine Protease 2 (TMPRSS2), AXL Receptor Tyrosine Kinase (AXL Receptor Tyrosine Kinase, AXL), FURIN (Pair Basic amino Acid cleaning Enzyme, FURIN) and the like in the host cells. On the other hand, SARS-CoV-2 can persistently infect multiple organs and evade attack by the immune system through constant variation. Therefore, the antiviral strategy of simultaneously targeting a plurality of new crown host factors and the virus can inhibit a plurality of infection steps of SARS-CoV-2, thereby preventing and treating the infection of the new crown virus and mutant strains thereof in a broad spectrum.
The RNA G-Quadruplex (RG 4) is an atypical nucleic acid secondary structure, is distributed in mRNA and non-coding RNA, participates in the processes of shearing, transporting and translating mRNA, synthesizing non-coding RNA and the like, and regulates the expression of various genes and the occurrence and development of diseases. Based on its unique biological functions, RG4 has gradually become a target for the treatment of various diseases such as cancer, neurological diseases, infectious diseases, metabolic diseases, etc. RG4 is found to be present in the genomes of various pathogenic viruses and is involved in regulation of the virus life cycle, including Human Immunodeficiency Virus (HIV), ebola virus (EBOV), marburg virus (MARV), severe acute respiratory syndrome coronavirus (SARS-CoV), hepatitis C Virus (HCV), zika virus (ZIKV) and the like. Recent studies have found that there are multiple RG4 structures in SARS-CoV-2 genomic RNA, suggesting that RG4 may be involved in viral replication and assembly. In addition, research has found that RG4 structures exist in mRNA of a plurality of new crown host factors such as ACE2, TMPRSS2 and the like, and RG4 inhibits the virus infection process by inhibiting the expression of the host factors. Therefore, RG4 is taken as a drug development target, possibly has a broad-spectrum antiviral effect of simultaneously targeting SARS-CoV-2 and a host factor thereof, and can provide an effective method for dealing with COVID-19 pandemics. Up to now, no clinical drugs against SARS-CoV-2 based on the RG4 structure have appeared.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel coronavirus resistant medicament taking RNA G-quadruplex as a target spot and a screening method thereof, the clinical medicament obtained by the screening method inhibits SARS-CoV-2 infection by down-regulating SARS-CoV-2 key host gene expression, and the medicament obtained by the screening method can be directly applied to a human body, thereby effectively solving the problem that the developed novel coronavirus resistant medicament can be applied to the human body by needing to be subjected to clinical tests firstly.
An anti-neocoronavirus medicine using RNA G-quadruplex as target point includes topotecan or berbamine.
A method for screening anti-new coronavirus medicines by taking an RNA G-quadruplex as a target spot comprises the following steps:
(1) Screening to obtain a drug compound with stable G-quadruplexes, and screening out drugs which are approved to enter clinic;
(2) The computer molecule Docking technology is utilized to screen out the medicine which is stably combined with the G-quadruplex, and then the compound which is scored by Docking and comprehensively ranked at the first two positions is screened out from the medicine, namely the anti-new coronavirus medicine.
Further, the computer molecular docking technology specifically operates as follows:
(1) Ligand molecule preparation: downloading the molecular structure of a pharmaceutical compound in a Chemical Book database, and simultaneously creating a new window in Discovery studio software and pulling in the molecular structure to construct an input library file;
(2) Preparation of receptor molecules: downloading an RG4 structure with the PBD number of 2KBP and 2M18 in a PBD database, loading Discovery studio software, opening a Define and Edit Binding Site module in a Receptor-Ligand Interactions unit of the Discovery studio software, defining the RG4 as a Receptor, and selecting the whole RG4 as a docking active Site;
(3) Molecule docking; in a Receptor-Ligand Interactions unit of Discovery studio software, a Dock Ligand module is opened, a Libdock mode is selected to carry out Docking of small molecules and RG4, a Number of Hotspots parameter is set to be 100 during Docking, a Docking toll parameter is set to be 0.25, a Docking preference mode is set to be High Quality, a Libdock score is obtained after the Docking is finished, and a Docking result with the highest score is introduced into Chimera X software for analysis.
The beneficial effects produced by the invention are as follows:
the invention uses RNA G-quadruplex as a target spot to screen and identify the anti-neocorolla small molecule drug, and provides a broader drug targeting strategy for preventing and treating SARS-CoV-2. The method determines and obtains two clinical drugs of topotecan (TPT) and berbamine (BBM), and proves that the TPT and BBM can inhibit SARS-CoV-2 and mutant virus strain from infecting host cells and organs by targeting new corona and host gene RG4 structure; meanwhile, the invention screens the existing medicines based on a screening strategy of 'medicine recycling', and can greatly shorten the time consumed in the research and development of the anti-neocoronaria medicine in clinical experiments.
Drawings
FIG. 1 is a flow chart showing the RG 4-based screening of anti-neocorolla drugs;
FIG. 2 is a diagram showing the in silico molecular docking screening of anti-neocorona drugs that bind to RG4 structures;
FIG. 3 shows the MST technology for detecting the binding of anti-neocorona drug and RG4 structure in the neocorona key host gene; detecting the binding capacity of RG4 and TPT in TMPRSS2; detecting the binding capacity of RG4 and BBM in TMPRSS2; detecting the combining capacity of RG4 and TPT in ACE2; detecting the binding capacity of RG4 and BBM in ACE2;
FIG. 4 shows that TPT and BBM inhibit intracellular and exogenous ACE2 and TMPRSS2 expression by RG 4; TPT and BBM inhibit the expression of exogenous ACE2 of cells through RG 4; TPT and BBM inhibit the expression of exogenous TMPRSS2 of cells through RG 4; TPT and BBM inhibit the expression of ACE2 and TMPRSS2 endogenous to the cells;
FIG. 5 shows that TPT and BBM inhibit SARS-COV-2 infection of host cells; TPT and BBM inhibit SARS-COV-2 infection of hACE2-293T cells; TPT and BBM inhibit SARS-COV-2 infection of H1299 and Vero-E6 cells; TPT and BBM inhibit SARS-COV-2 mutant strains P.1 and B.1.617.2 from infecting hACE2-293T, H1299 and Vero-E6 cells;
FIG. 6 shows that TPT and BBM inhibit SARS-COV-2 infection in mice; a, a flow chart of a mouse infected by SARS-COV-2 pseudovirus; TPT and BBM inhibit mouse lung TMPRSS2 expression; TPT and BBM inhibit SARS-COV-2 infection of mouse lung.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings.
An anti-neocoronavirus medicine with G-quadruplex as target spot comprises topotecan or berbamine.
1. Screening of anti-neocorolla drugs binding to RG4 structure
(1) Screening and obtaining drug compounds with stable G-quadruplexes from compounds recorded in the existing database and documents, wherein the total number of the drug compounds is 69, and using the drug compounds as a ligand library for subsequent drug screening; drugs approved by the United states Food and Drug Administration (FDA) or National Drug Products Administration (NMPA) for clinical use, including adriamycin, epirubicin, mitoxantrone, bleomycin, topotecan, berbamine, berberine, palmatine or tetrandrine, are screened out, wherein adriamycin, epirubicin, mitoxantrone, bleomycin have significant pulmonary and cardiotoxicity and are excluded;
(2) And (3) screening out the medicines which are stably combined with the G-quadruplex and have the toxicity of the human body from the rest 5 medicines by utilizing a computer molecular Docking technology, and screening out the compounds which are scored by Docking and have the first two comprehensive ranks from the medicines, namely the anti-new coronavirus medicines.
The computer molecular docking experiments were as follows: 1) Ligand molecule preparation, namely downloading small molecular structures with CAS numbers of 123948-87-8 (topotecan and TPT), 478-61-5 (berbamine and BBM), 2086-83-1 (berberine), 3486-67-7 (palmatine) and 518-34-3 (tetrandrine) from a Chemical Book database, and simultaneously creating a new window in Discovery studio software and pulling in the small molecules to create an input library file; 2) Preparing Receptor molecules, downloading RG4 structures with PBD numbers of 2KBP and 2M18 from a PBD database, loading Discovery studio software, opening a Define and Edit Binding Site module in a Receptor-Ligand Interactions unit of the Discovery studio software, defining the RG4 as a Receptor, and selecting the whole RG4 as a docking active Site; 3) And (2) molecule docking, namely opening a Dock lip module in a Receptor-Ligand Interactions unit of Discovery studio software, selecting a Libdock mode to Dock small molecules with RG4, setting a Number of Hotspots parameter to be 100, setting a docking toll parameter to be 0.25, setting a docking preference mode to be High Quality during docking, obtaining a Libdock score after the docking is finished, and importing the highest docking result into Chimera X software for analysis.
As shown in fig. 2, after the molecular structures of the above 5 drugs are molecularly docked with 2KBP and 2M18 of the telomere RG4 structure, respectively, the Libdock score of TPT, BBM and RG4 binding is higher, the comprehensive ranking is located at the first two digits, and when the binding conformation is analyzed, the small molecules of TPT and BBM can be embedded into the base of RG4, which indicates that TPT and BBM are well bound with the telomere RG4 structure, and TPT and BBM are the desired compounds.
2. MST technology for detecting combination of anti-neocorona drug and RG4 structure in neocorona key host gene
The MST technology is used for detecting the fluorescence intensity of RNA thermal surge change under the concentration of a gradient compound, and the dissociation constant KD is calculated to evaluate the affinity of the small molecule and the RNA.
MST experiment: 1) Preparing RNA working solution, heating 100-300nM CY5-labeled RNA sample at 95 ℃ for 5 minutes, cooling to 25 ℃ at 0.5 ℃/minute, and annealing to form RNA secondary structure; 2) Preparing a ligand molecule and RNA mixed solution, namely performing gradient dilution on the ligand molecule according to the proportion of 1:1 to obtain 16 ligand molecule solutions with gradient concentrations, taking 5 mu l of ligand molecule solution with each concentration to an EP (EP) tube, respectively adding 5 mu l of RNA working solution, uniformly mixing, and sucking into a capillary tube; 3) Performing on-machine detection, arranging capillaries on a sample platform of a Monolith NT.115 instrument according to the concentration sequence of ligand molecule dilution, wherein the test conditions are as follows: 20% LED, medium MST power, data were analyzed using Nano tester Technologies and curves were fitted to calculate dissociation constant KD values. The RNA sequences used in the present invention are PQS-675-WT (Tmprss 2): CY5-GGGCGGGCGGCCUGCAGGGACAUGGG; PQS-675-MUT (Tmprss 2): CY5-GAGCGAGCGGCCUGCAGAGACAUGAG; PQS-2302-WT (Ace 2): CY5-GGGGAGGAGG; PQS-2302-MUT (Ace 2): CY5-GAGAAAGAGA.
As shown in FIG. 3, RG4 sequences of TMPRSS2 and ACE2 both bound TPT with KD values of 383.01nM and 29.81. Mu.M, respectively; after RG4 key sites are mutated, the binding capacity of the RNA sequence and TPT is obviously weakened, and a normal binding curve cannot be fitted. Similarly, the RG4 sequences of TMPRSS2 and ACE2 can also bind BBM with KD values of 10.78nM and 264.76. Mu.M, respectively; after the RG4 structure forming site mutation, the binding capacity of the RNA sequence and BBM is obviously weakened, and the normal binding curve cannot be fitted. The results above confirm at the molecular level that TPT, BBM are able to interact with neocorona related RG4, both RG4 ligands.
3. TPT and BBM inhibit expression of intracellular and exogenous ACE2 and TMPRSS2 through RG4
Respectively cloning ORF regions of ACE2 and TMPRSS2 into a PC3.1 vector to obtain overexpression plasmids of ACE2 and TMPRSS 2; g of RG4 key site in ORF region of ACE2 and TMPRSS2 is mutated into A to construct corresponding ACE2-G4MUT and TMPRSS2-G4MUT plasmids. The plasmid is transfected into H1299 cells, the cells are treated by 8 mu M TPT or 8 mu g/ml BBM respectively after being transfected for 24 hours, and the total protein of the cells is collected after being treated by drugs for a western-blot experiment.
As shown in fig. 4, TPT and BBM significantly reduced the protein expression levels of exogenous ACE2, TMPRSS 2; after RG4 site mutation, the treatment has no obvious difference to protein expression level, and proves that TPT and BBM can inhibit SARS-COV-2 key host gene expression through RG 4. In addition, 8 μ M TPT, 8 μ g/ml BBM treatment of neocoronaviral susceptible cells H1299, vero-E6 (TMPRSS 2 deletion) were able to down-regulate the expression of endogenous ACE2 and TMPRSS 2.
4. TPT and BBM (tyrosine phosphatase and Bbbm) for inhibiting SARS-COV-2 and mutant strain thereof from infecting host cells
As SARS-CoV-2 is very contagious, it must be performed in a three-level biosafety laboratory with high safety class and high operation cost to ensure safety. In order to reduce the cost and shorten the drug development time, the invention selects SARS-COV-2 Pseudovirus (Pseudovirus) without infectivity to carry out experiments, and can simulate the infection process of identifying the euvirus and the receptor and entering host cells.
Infection and detection of cell pseudovirus: 1) The cells were treated by collecting 1.5X 10 cells of hACE2-293T, H1299 and Vero-E6 in good growth state 4 Inoculating the cells/ml to a 96-well plate, sucking out the culture medium when the cell density is about 60-80%, and replacing with a drug working solution; after 6 hours, virus solution (MOI = 0.1) was added; after adding the virus solution for 18 hours, replacing the culture medium as a drug working solution, and continuously incubating for 24 hours to detect luciferase activity; 2) Detecting Luciferase activity, wherein SARS-CoV-2 pseudovirus is provided with a fluorescein (Luciferase) label and is used for detecting virus invasion, a 96-well plate is placed at room temperature for 10 minutes, 100 mu l of Luciferase Assay Buffer is added into each well, reaction is carried out for 3 minutes, and fluorescence is detected by a microplate reader.
As shown in FIG. 5, when hACE2-293T cells were treated with a gradient of TPT or BBM, both TPT and BBM inhibited SARS-CoV-2 entry into the cells in a dose-dependent manner. In two new crown-susceptible cell lines of H1299 and Vero-E6, the inhibition rate of 8 mu M TPT and 8 mu g/ml BBM on virus infection is over 80 percent, which indicates that TPT and BBM can effectively inhibit SARS-CoV-2 infection. In addition, the invention proves that TPT and BBM also obviously inhibit SARS-CoV-2 mutant strains P.1 and B.1.617.2 mutant strains from entering host cells, and have antiviral infection activity, thereby indicating that TPT and BBM are extremely potential drugs for resisting new coronavirus infection.
5. TPT and BBM inhibit SARS-COV-2 infected mouse
AAV9-hACE2 is used to construct a new corona susceptible mouse model, and the effect of TPT and BBM on SARS-CoV-2 infection is verified at animal level by SARS-CoV-2 pseudovirus infection.
Establishing a new corona susceptible mouse model and detecting a pseudovirus: as shown in FIG. 6A, AAV9-hACE2 was injected intrathoracic into 8-week-old C57BL/6J mice (Day 0), and one week later, SARS-CoV-2 pseudovirus-mimicking virus infection was intrathoracic injected (Day 7). Experimental mice were randomly divided into three groups of TPT, BBM, and NC (Negative Control), 6 mice per group, and the mice were administered 1 time per Day from 1 Day before infection (Day 6) to 7 days after infection (Day 7) for 9 consecutive days, all of which were given by intraperitoneal injection. Wherein the TPT group was administered at a dose of 1mg/kg (dissolved in 20% SBE-. Beta. -CD), the BBM group was administered at a dose of 50mg/kg (dissolved in physiological saline), and the NC group was injected with an equivalent amount of 20% SBE-. Beta. -CD solution containing no drug. On Day 8 of pseudovirus infection (Day 15), mice were subjected to in vivo fluorescence detection using a small animal imager and the fluorescence intensity was quantified.
As shown in fig. 6, the total photon flux values of the TPT and BBM groups were significantly reduced compared to the NC group, indicating that TPT and BBM have the ability to resist viral infection in mice. Meanwhile, detection in the collected lung tissues of the mice shows that TPT and BBM can obviously reduce the protein expression of TMPRSS2 in the lungs of the mice, which indicates that TPT and BBM can inhibit virus infection through RG4 structures in new coronary key host factors.
Claims (3)
1. An anti-neocoronaviruse medicine taking RNA G-quadruplex as a target spot is characterized by comprising topotecan or berbamine.
2. A method for screening anti-neocoronavirus medicines by taking an RNA G-quadruplex as a target point is characterized by comprising the following steps of:
(1) Screening to obtain a drug compound with stable G-quadruplexes, and screening out drugs which are approved to enter clinic;
(2) The computer molecule Docking technology is utilized to screen out the medicine which is stably combined with the G-quadruplex, and then the compound which is scored by Docking and comprehensively ranked at the first two positions is screened out from the medicine, namely the anti-new coronavirus medicine.
3. The method for screening anti-neocoronavirus medicines with RNA G-quadruplex as a target point of claim 2, wherein the computer molecular docking technology is specifically operated as follows:
(1) Ligand molecule preparation: downloading the molecular structure of the drug compound in a database, simultaneously creating a new window in Discovery studio software and pulling in the molecular structure to establish an input library file;
(2) Preparation of receptor molecules: downloading an RG4 structure with the PBD number of 2KBP and 2M18 in a database, loading Discovery studio software, opening a Define and Edit Binding Site module in a Receptor-Ligand Interactions unit of the Discovery studio software, defining the RG4 as a Receptor, and selecting the whole RG4 as a docking active Site;
(3) Molecule docking; in a Receptor-Ligand Interactions unit of Discovery studio software, a Dock module is opened, a Libdock mode is selected to carry out docking of small molecules and RG4, a Number of hosts parameter is set to be 100 during docking, a docking permission parameter is set to be 0.25, a docking preference mode is set to be High Quality, a Libdock score is obtained after docking is finished, and a docking result with the highest score is introduced into Chimera X software for analysis.
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