CN113041247A - Application of imatinib in medicine for preventing and treating novel coronavirus and complications - Google Patents
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- CN113041247A CN113041247A CN202110429660.1A CN202110429660A CN113041247A CN 113041247 A CN113041247 A CN 113041247A CN 202110429660 A CN202110429660 A CN 202110429660A CN 113041247 A CN113041247 A CN 113041247A
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Abstract
The invention relates to the technical field of medicinal chemistry, in particular to application of imatinib in a medicament for preventing and treating novel coronavirus and complications, and the imatinib provided by the invention not only can effectively inhibit virus infection, but also can further improve metabolic complications caused by the novel coronavirus; can effectively improve various metabolic diseases regulated and controlled by ACE2 in RAS system; high safety, small side effect, wide applicability and being beneficial to rapid popularization.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to application of imatinib in a medicine for preventing and treating novel coronavirus and complications.
Background
COVID-19 is a global epidemic that is still rapidly spread worldwide. By 2021.3.19, COVID-19 has caused 120915219 infections and 2674078 deaths in 216 countries and regions worldwide, severely compromising the global human health.
Angiotensin converting enzyme ACE2(Angiotensin-converting enzyme 2) is a main receptor for SARS-CoV and SARS-CoV-2 invading host, previous research focuses on inhibiting the virus invasion by inhibiting the binding of ACE2 and the virus Spike protein, but neglects the effect of ACE2 as an important molecule for antagonizing RAS system after being attacked by virus in organism metabolism. The invasion of the cells by the virus causes the internalization and the shedding of ACE2, which causes the down-regulation of ACE2 on the membrane, so that the damaged ACE2 may bring certain metabolic damage, and the condition of a new coronary patient with metabolic basic diseases (such as hypertension, heart disease, diabetes, obesity and the like) is easy to worsen. Meanwhile, the new coronary patients often have symptoms of hepatic steatosis, glomerular injury, vascular endothelial dysfunction and the like, and the body of the new coronary patients has glycolipid metabolic disorders such as hyperglycemia, hypertension, high-density lipoprotein cholesterol reduction and the like. According to the research report, 5% -29% of patients with COVID-19 suffer from new onset diabetes and are accompanied with poor prognosis of diseases; venous thromboembolism in 25% -69% of patients with severe COVID-19 is a significant cause of death. Thus, COVID-19 is not only a pneumonitis disease, but is also a systemic metabolic disease involving multiple organ damage.
The current methods for treating covi-19, including antiviral, antibody, anti-inflammatory and immunomodulatory therapies, are rare to show strong therapeutic effects. Although the COVID-19 vaccine is inoculated in a few developed countries and can enhance the body defense capability, the current vaccine market supply is seriously insufficient, the protection time is short, and a large number of virus variants cause great reduction or ineffectiveness of antibody effect, more importantly, the popularization of vaccination is difficult to achieve in non-developed countries, and all the factors influence the thorough elimination of new coronavirus. On the other hand, the complications caused by COVID-19 still lack attention, and specific medicines aiming at the complications are not available. Therefore, elucidating the molecular mechanisms of COVID-19 and its complications and performing clinical drug development against relevant targets is a global important challenge and major need to develop more effective, more economical, and less side-effect antiviral drugs to protect susceptible populations and to treat the metabolic complications from COVID-19, and will remain the key to our ultimate success in overcoming COVID-19.
Imatinib, a tyrosine kinase inhibitor, selectively inhibits BCR/ABL (fusion gene) kinase activity and is commonly used to treat chronic myelogenous leukemia, myeloid leukemia (CML). Imatinib has been proved to inhibit SARS-CoV and MERS-CoV virus invasion, but its further function is rarely studied deeply. Detailed cell experiments and animal experiments prove that Imatinib not only can effectively inhibit the infection of new coronavirus, but also can well improve metabolic complications caused by the virus. Because the Imatinib is a clinical medicine, the safety is high, the side effect is less, and the time is short, the Imatinib is an ideal and rapid medicine for preventing and treating the new coronary pneumonia.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the application of imatinib in a medicine for preventing and treating novel coronaviruses and complications.
The purpose of the invention is realized by the following technical scheme:
imatinib (Imatinib) with molecular formula of C29H31N7O, CAS number 152459-95-5, structural formula as follows:
use of imatinib in a medicament for the prophylaxis and treatment of novel coronaviruses.
Application of imatinib in medicine for preventing and treating complications caused by novel coronavirus.
Use of imatinib as a medicament for activating ACE2 activator.
Application of imatinib in medicines for preventing and treating metabolic diseases.
The imatinib is applied to drugs for preventing and treating obesity, diabetes, cardiovascular diseases, pulmonary and renal fibrosis and atherosclerosis.
New coronary infection can cause hyperglycemia, hypertension, low HDL-C, glomerular and vascular dermatitis injury, thrombus and the like, metabolic diseases corresponding to the symptoms, such as diabetes, hypertension, diabetic nephropathy and atherosclerosis, are subjected to bioinformatics analysis, and common differential expression genes and regulation and control pathways of the four metabolic diseases are searched. In the DisGeNET and OpenTarget databases, 400 related genes before four metabolic diseases of diabetes, hypertension, diabetic nephropathy and atherosclerosis are respectively selected, intersection is respectively taken to obtain 48 genes and 72 genes, the intersection is further taken to obtain 20 genes, and the 20 genes are core common genes of the four metabolic diseases. On the basis, the 20 genes are compared with the expression profile of the new crown infection related genes, and the ACE2 changes in a plurality of new crown infection related gene profiles uniformly and is reduced in expression after infection, which indicates that the ACE2 may be a key molecule for regulating and controlling the glycolipid metabolic disorder of the new crown infection. And the ACE2 is knocked down in an in vitro cell line, and the obvious enhancement of the expression of genes related to inflammation, fibrosis and atherosclerosis and the disturbance of genes related to glycolipid metabolism are found. Similarly, in an ob/ob mouse metabolic disorder model, overexpression of ACE2 can reduce fasting plasma glucose, improve glucose tolerance and insulin resistance, reduce total cholesterol, low density lipoprotein and high density lipoprotein in plasma, reduce inflammatory factor in blood and kidney injury factor KIM-1. Both liver fat and kidney glycogen are reduced. At the same time, gluconeogenesis, glycogen synthesis, glucose uptake and fat synthesis pathways in the liver, kidney and aorta are all significantly improved after overexpression of ACE 2. These results indicate that activation of the ACE2 pathway can significantly ameliorate metabolic disorders. Therefore, we next focused on finding ACE2 activators. And performing multiple screening by using a Tianhe No. 2 supercomputer and a CMAP database to finally obtain 15 candidate small molecules which can potentially activate ACE2 and inhibit virus infection. Further screening Imatinib as a medicine for finally activating ACE2 to improve metabolic disorder of new coronary patients through a large number of in vitro cell experiments. And then further verifying the metabolic improvement effect of the Imatinib in a high-fat mouse model, and finally verifying the virus inhibition effect of the Imatinib in SARS-CoV-2 and pseudovirus experiments and reversing metabolic gene disorder caused by virus infection.
Compared with the prior art, the invention has the following technical effects:
1. the Imatinib provided by the invention not only can effectively inhibit virus infection, but also can further improve metabolic complications caused by new coronavirus.
2. The Imatinib provided by the invention is an enzyme activity direct agonist of ACE2, and can effectively improve various metabolic diseases regulated by ACE2 in an RAS system.
3. The Imatinib provided by the invention is a clinical drug, has high safety, small side effect and wide applicability, and is beneficial to rapid popularization.
Drawings
Figure 1 is a process diagram of imatinib binding and dissociation from ACE 2;
figure 2 is a graph of the results of an imatinib activated ACE2 enzyme activity assay;
FIG. 3 is a diagram showing the results of RT-PCR detection of inflammation and glycolipid metabolism genes by HUVEC cells;
FIG. 4 is a graph showing the results of RT-PCR assay after HUVEC cells were treated with 4 inflammatory factors (G6pc, Glut2, Ppar α, Ppar γ);
FIG. 5 is a graph of the results of GTT and ITT tests on mice on a high fat diet;
FIG. 6 is a graph of fasting blood glucose and Insulin measurements for high fat diet mice;
FIG. 7 is a graph showing the results of measurement of the inflammatory factor TNF α, kidney injury molecule KIM-1 in the blood of mice on a high-fat diet;
FIG. 8 is a graph of the results of glutamic acid transaminase ALT and aspartate aminotransferase AS assays in high fat diet mice;
FIG. 9 is a graph of liver oil red O staining in high fat diet mice;
FIG. 10 is a graph showing the quantitative results of liver oil red O in mice on a high-fat diet;
FIG. 11 is a staining pattern of glycogen in kidney of high fat diet mouse;
FIG. 12 is a graph showing the results of the quantification of glycogen in kidney of mice fed with a high-fat diet;
FIG. 13 is a diagram showing the expression of glycolipid metabolism-related genes in the liver of a high-fat diet mouse;
FIG. 14 shows the expression of glycolipid metabolism-related genes in aortic tissues of mice with high fat diet;
FIG. 15 is a graph showing the change in Ang II/Ang- (1-7) turnover in blood of high-fat diet mice;
FIG. 16 is a graph showing the change of ACE2 enzyme activity in the renal aortic tissue of a mouse with a high fat diet;
FIG. 17 is a graph showing the results of imatinib inhibition of viral invasion and amelioration of metabolic gene disorders following viral infection;
FIG. 18 is a graph showing GFP fluorescence expression in a pseudovirus-invaded cell assay;
FIG. 19 is a graph showing the statistical fluorescence intensity of the experiment for invading pseudoviruses into cells.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The test methods used in the following experimental 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
Use of imatinib as a medicament for activating ACE2 activator.
1) Surface Plasmon Resonance (SPR) method: purified ACE2 protein was coupled to a CM7 sensor chip and the Imatinib solution was delivered to the surface of the sensor chip via a microinjected flow cartridge and Biacore T100 tracked the binding and dissociation of Imatinib to ACE 2.
2) After well-grown HUVEC cells are lysed by ACE2 Lysis, protein concentration is measured by BCA, 20ug of protein is taken to be co-incubated with Imatinib for 30min, substrate is added for reaction, and fluorescence intensity is detected in a kinetic mode within 5 min.
3) HUVEC cells were treated with Imatinib for 16h, the collected cells were lysed with Trizol, RNA was extracted, and genes for inflammation and glycolipid metabolism were detected by RT-PCR.
The experimental result proves that Imatinib can directly bind with ACE2 and activate the enzyme activity, and Imatinib can obviously activate ACE2 and the glycolipid metabolism and inflammation genes downstream of the pathway of ACE. FIG. 1 shows that Imatinib binds directly to ACE2, FIG. 2 shows that Imatinib activates ACE2 enzyme activity and has a dose-dependent effect, and drug group-1 (1.5nM) and drug group-2 (15nM) are two different dose-treated groups of Imatinib. FIG. 3 shows that Imatinib activates glycolipid metabolism and inflammation-related genes downstream of the ACE2 pathway. Drug-1 (1 μ M), drug-2 (5 μ M), drug-3 (25 μ M) were three different dose treatment groups of Imatinib. P < 0.05; p < 0.01; p < 0.001.
Example 2
Application of imatinib in drugs for preventing and treating metabolic diseases and application in drugs for preventing and treating complications caused by novel coronaviruses.
1) HUVEC cells were co-treated with 4 inflammatory factors (TNF. alpha., IL-4, IL-6, INF. gamma.) for 32h, then treated with Imatinib for 16h, the cells were harvested and lysed with Trizol, RNA was extracted, and genes for inflammation and glycolipid metabolism were detected by RT-PCR.
The new coronary infection causes inflammatory factor storm, the umbilical vein endothelial cells are co-treated with 4 inflammatory factors in an in vitro cell line to simulate the cell state of the new coronary virus infection, and Imatinib can improve glycolipid gene disorder caused by the inflammatory factors. Experimental results prove that Imatinib can save glycolipid metabolic disorder caused by inflammatory factors. FIG. 4 is a graph showing the results of RT-PCR detection after treatment with inflammatory factors G6pc, Glut2, Ppar α, Ppar γ. Drug-1 (1 μ M), drug-2 (5 μ M), drug-3 (25 μ M) were three different dose treatment groups of Imatinib. O is blank control, □ is inflammatory factor treated group, Δ is inflammatory factor + drug treated group-1 (1 μ M), Vis inflammatory factor + drug treated group-2 (5 μ M),. diamond is inflammatory factor + drug treated group-3 (25 μ M). # is the comparison between the inflammatory factor treated group and the control blank group, and between the inflammatory factor + drug group and the inflammatory factor treated group. # p < 0.05; # p < 0.01; # p < 0.001. P < 0.05; p < 0.01; p < 0.001.
Example 3
The imatinib is applied to medicines used as an ACE2 activator, medicines used for preventing and treating metabolic diseases, and medicines used for preventing and treating obesity, diabetes, cardiovascular diseases, pulmonary and renal fibrosis and atherosclerosis.
1) 60% high fat fed C57BL/6J mice were modeled for 6 months, 250mg/kg Imatinib was administered by daily gavage for 4 weeks, fasting for 15h, after glucose injection, tail vein blood test for GTT at 30, 60, 90, 120min, fasting for 6h, and after insulin injection, tail vein blood test for ITT and fasting blood glucose at 30, 60, 90, 120 min.
2) The mouse liver and kidney were stained with oil red O and glycogen, respectively. And (3) taking mouse serum and liver for lipid detection.
3) Mouse serum ELISA was used to determine the conversion rates of the activities of the inflammatory factor TNF α, the kidney injury factor KIM-1 and ANG/ANG- (1-7).
4) Extracting RNA from mouse liver and kidney tissues, and detecting gluconeogenesis, glucose uptake, fat synthesis and inflammation related gene expression by RT-PCR.
5) The kidney and aorta tissues were taken to extract protein, protein concentration was measured by BCA, and enzyme activity was measured by ACE2 enzyme activity kit.
The test results are shown below: fig. 5 is a graph showing the results of a Glucose Tolerance Test (GTT) and an Insulin glucose tolerance test (ITT), fig. 6 is a graph showing the results of measurement of fasting blood glucose and Insulin, fig. 7 is a graph showing the results of measurement of an inflammatory factor TNF α and a kidney injury molecule KIM-1 in blood, fig. 8 is a graph showing the results of measurement of glutamate aminotransferase ALT and aspartate aminotransferase AS, fig. 9 is a graph showing the staining of liver oil red O, fig. 10 is a graph showing the results of quantification of liver oil red O, fig. 11 is a graph showing the staining of kidney glycogen, fig. 12 is a graph showing the results of quantification of kidney glycogen, and fig. 13 is a graph showing the expression of a gene involved in glycolipid metabolism in the liver; FIG. 14 is a graph showing the expression of glycolipid metabolism-related genes in aortic tissues, FIG. 15 is a graph showing the change in the conversion rate of Ang II/Ang- (1-7) in blood, and FIG. 16 is a graph showing the change in the activity of ACE2 enzyme in renal aortic tissues. # is an analogy between the DIO group and the Lean group, $ is an analogy between the DIO + drug group and the DIO group. # p < 0.05; # p < 0.01; # p < 0.001. P < 0.05; $ p < 0.01; $ p < 0.001. Experimental results prove that Imatinib can obviously reduce blood sugar, insulin resistance, total cholesterol content in liver and serum, glutamic acid transaminase ALT and aspartate aminotransferase AST content in serum, relieve inflammation, relieve kidney injury, enhance ACE2 enzyme activity, and improve glycolipid metabolism related gene disorder caused by high fat diet in liver, kidney and aorta.
Example 4
The application of imatinib in a medicament for preventing and treating novel coronavirus and the application of imatinib in a medicament for preventing and treating complications caused by the novel coronavirus.
1) After 6h of treating HUVEC of human umbilical vein endothelial cells by Imatinib, cells are infected by SARS-CoV-2 virus for 18h, the cells are lysed by Trizol, RNA is extracted, and expression of glycolipid metabolism related genes Glut2, Pgc1 alpha, Ppar alpha and Ppar gamma is detected by RT-PCR.
2) After 6h of treating HUVEC of human umbilical vein endothelial cells by Imatinib, pseudoviruses infect the cells for 18h, and GFP fluorescence expression is observed under a microscope and fluorescence intensity is counted.
The experimental results are as follows: FIG. 17 shows that Imatinib ameliorates metabolic gene abnormalities following SARS-CoV-2 infection. FIGS. 18 and 19 are graphs showing the pseudovirus infection inhibition efficiency and fluorescence intensity of Imatinib in a pseudovirus-invaded cell assay. P < 0.05; p < 0.01; p < 0.001. Experimental results prove that Imatinib can effectively inhibit virus infection and improve metabolic gene disorder caused by virus infection.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (5)
1. Use of imatinib in a medicament for the prophylaxis and treatment of novel coronaviruses.
2. Application of imatinib in medicine for preventing and treating complications caused by novel coronavirus.
3. Use of imatinib as a medicament for activating ACE2 activator.
4. Application of imatinib in medicines for preventing and treating metabolic diseases.
5. The imatinib is applied to drugs for preventing and treating obesity, diabetes, cardiovascular diseases, pulmonary and renal fibrosis and atherosclerosis.
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