CN111053909A - Application of 2019-nCoV3CL hydrolase inhibitor and IL-6 monoclonal antibody in preparation of medicine for treating neocoronary pneumonia - Google Patents
Application of 2019-nCoV3CL hydrolase inhibitor and IL-6 monoclonal antibody in preparation of medicine for treating neocoronary pneumonia Download PDFInfo
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Abstract
The invention discloses an application of a 2019-nCoV3CL hydrolase (Mpro) inhibitor and interleukin-6 (IL-6) monoclonal antibody in preparation of a medicine for treating neocoronary pneumonia, and belongs to the technical field of medicines. By establishing a co-culture model of Vero E6 cells inoculated with new coronavirus 2019-nCoV and macrophage Thp-1, the process that the new coronavirus generates inflammatory reaction is simulated in a cell body, the combined application of an inhibitor aiming at 2019-nCoV Mpro and a monoclonal antibody for reversing macrophage M1 type proinflammatory polarization is designed, and the result shows that the combined application of the inhibitor and the monoclonal antibody is favorable for curing and prognosis recovery of the new coronary pneumonia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a 2019-nCoV3CL hydrolase (Mpro) inhibitor and interleukin-6 (IL-6) monoclonal antibody in preparation of a medicine for treating new coronary pneumonia.
Background
It is known that 2019-nCoV3CL hydrolase participates in replication of new coronavirus in human body, and the purpose of treating new coronary pneumonia can be achieved by inhibiting the action of the hydrolase. However, in the body of a new coronary patient, macrophage M1 type is over-activated and secretes excessive proinflammatory factors and chemokines due to stimulation of viruses, and macrophage M2 type is inhibited from being activated, so that inflammatory damaged tissues cannot be repaired, a positive feedback cycle is formed, a threshold value is broken through and the tissues are out of control, and finally a cytokine storm is formed, so that severe immune damage to the lung and other organs is caused. Therefore, treatment of new coronary pneumonia requires not only inhibition of viral replication in vivo, but also reversal of key cytokines that induce inflammatory storms, blocking of some of the monocyte/macrophage M1 polarization and its signaling, promotion of monocyte/macrophage M2 polarization, and reduction and repair of inflammatory response damage to the patient's lung tissues and multiple organs.
At present, aiming at the new coronary pneumonia, no specific antiviral drug exists, the treatment mainly comprises symptomatic treatment and supporting treatment, the symptomatic treatment is that oxygen is supplemented when hypoxemia occurs in a patient, and water electrolyte balance is corrected when water electrolyte imbalance occurs; supportive care is the treatment of maintaining and assisting the body's functions, such as supplementing water, electrolytes, vitamins and nutrients. The use of hormones (e.g. glucocorticoids) to suppress immunity against the attack of autoimmunity on lung tissue avoids further lung tissue damage, but this simultaneously suppresses the immune response making it difficult for the immune system to complete the formation of autoantibodies critical in the course of viral infection, coupled with the high levels of hormone are highly susceptible to major irreversible side effects. Although a high-resolution crystal structure of 2019-nCoV hydrolase (Mpro) of the new coronavirus is obtained at present, the existing molecular drugs can be screened by comprehensively utilizing a strategy of combining virtual screening and enzymatic testing, and the proliferation of the virus in a patient body is inhibited from the replication level of the virus. However, the new coronavirus is different from SARS and is not dangerous in some patients, and the inflammation storm caused by the excessive activation of the immune system caused by infection, medicine or some diseases after the later administration is mainly caused, and the multi-organ function failure caused by the inflammation storm has not yet attracted attention.
Disclosure of Invention
The invention aims to provide an application of a 2019-nCoV3CL hydrolase (Mpro) inhibitor and interleukin-6 (IL-6) monoclonal antibody in preparation of a medicine for treating new coronary pneumonia, and the combined use of the 2019-nCoV3CL hydrolase (Mpro) inhibitor and the interleukin-6 (IL-6) monoclonal antibody can inhibit excessive M1 polarization of macrophages in a patient, control the generation of inflammatory storm, promote M2 polarization of the macrophages and promote the repair of damaged tissues of the pneumonia patient.
In order to achieve the above object, the present invention adopts the following technical means:
application of 2019-nCoV3CL hydrolase inhibitor and interleukin-6 monoclonal antibody in preparation of medicine for treating neocoronary pneumonia.
Further, the 2019-nCoV3CL hydrolase inhibitor is selected from indinavir, saquinavir, lopinavir, carfilzomib or ritonavir.
Further, the 2019-nCoV3CL hydrolase inhibitor is carfilzomib or saquinavir.
Unlike symptomatic treatments of existing therapeutic approaches, the present invention is directed to the treatment of new coronaviruses, on the one hand taking into account the inhibition of transcription of new coronaviruses in vivo by inhibition of the 2019-nCoV hydrolase. On the other hand, by partially inhibiting the pro-inflammatory action of macrophage M1 type, a partial immune response is retained; promoting M2 type polarization, and repairing damaged tissue and organ, thereby reversing excessive polarization of immune system caused by new corona virus, and preventing multiple organ failure caused by inflammation storm in later stage of new corona patient mainly due to in vivo inflammation storm outbreak. The two aspects act simultaneously, and the later recovery of a new corona patient is considered while the new corona virus is treated.
The invention establishes a co-culture model of Vero E6 cells inoculated with new coronavirus 2019-nCoV and macrophage Thp-1, and simulates the process of generating inflammatory reaction of the new coronavirus in cells. The combined application of the 2019-nCoV Mpro inhibitor and the monoclonal antibody for reversing macrophage M1 type proinflammatory polarization is designed, and the combined application of the inhibitor and the monoclonal antibody is favorable for curing and prognosis recovery of the new coronary pneumonia.
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FIG. 1 shows a model of Vero E6 cell-Thp-1 cell co-culture seeded with 2019-nCoV in the present invention.
Detailed Description
2019A novel coronavirus (2019-nCoV, New crown for short) capable of infecting human is disclosed, and common symptoms after infection comprise respiratory symptoms, fever, cough, short breath, dyspnea and the like. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, renal failure, and even death. In clinical cases with new crowns, common upper respiratory tract inflammatory infections, the inflammatory reaction mainly occurs in the endothelial cells of the vascular wall of the lung, which causes a large amount of activated immune cells to flow into the lung, and at the same time, the vascular permeability is increased, and finally the patient dies from lung failure, acute respiratory distress syndrome and hypovolemic shock.
The pathogenesis of the virus is mainly that after the virus enters a human body, the outermost Spike protein (Spike protein) is combined with the human respiratory epithelial cell surface specific receptor angiotensin converting enzyme 2 (ACE 2 protein), then enters cells through the endocytosis of the cells, and then the virus genome RNA is directly used as a translation template to express the virus RNA polymerase. This enzyme is then used to complete the transcription and synthesis of sub-genomic RNA (sub-genomic RNA), the synthesis of mRNAs of various structural proteins, and the replication of viral genomic RNA. After the structural proteins and genomic RNA are replicated, new coronavirus particles are assembled at the endoplasmic reticulum of the host cell and secreted extracellularly by the golgi apparatus, completing their cycle.
The currently known novel coronavirus pneumonia 2019-nCoV3CL hydrolase (Mpro) is a key protein of the novel coronavirus, and the virus is used for replicating RNA (ribonucleic acid) and finally completing amplification in a human body. The invention uses the combination of small molecular drugs and Mpro protein to inhibit the action of hydrolase, thereby achieving the purpose of treating new coronavirus.
In the above process, the new coronavirus can induce an inflammatory response in the patient as an exogenous stimulus. Inflammation is a protective response reaction of an organism against exogenous or endogenous injury factors, and is a double sword for the organism, so that the inflammation reaction is favorable under general conditions and can protect the organism from being invaded by pathogens; however, abnormal inflammatory reactions are harmful to the body and are closely related to the occurrence and development of various diseases. Research has shown that macrophages play an important role in the regulation of inflammation, and in particular, the polarization and dynamic changes of macrophages play an important role in the development and progression of inflammatory diseases. Monocytes/macrophages, an important class of immune cells, can be polarized upon stimulation of inflammation into two types, the classical activation type (M1 type) or the alternative activation type (M2 type). M1 type macrophages have the functions of secreting proinflammatory factors and promoting Th1 and Th17 cellular immune responses, and kill pathogens, but hyperfunction of M1 type macrophages can cause body tissue damage and is related to pathogenesis of autoimmune diseases. The M2 type macrophage can secrete anti-inflammatory factor, induce Th2 cell immune response, inhibit inflammation, promote tissue repair and angiogenesis, and is beneficial to the recovery of inflammation course. High expression of ACE2 in a new coronary patient directly contacts with external lung tissue to form a main invasion object of a novel coronavirus, so that immune cells in the lung are over activated, macrophages are stimulated to be polarized to M1 type to generate a large amount of inflammatory factors, an inflammatory storm is formed through a positive feedback circulation mechanism, too much autologous cell injury is caused, a large amount of immune cells and tissue fluid are gathered in the lung, gas exchange between alveoli and capillary vessels is blocked, acute respiratory distress syndrome is caused, meanwhile, a large amount of cell contents in some patients are released into blood to cause wide and strong immune response, a large amount of various cytokines are rapidly generated, and the cytokine inflammatory storm is formed. In a new coronary patient, the polarization of M1 type is mainly mononuclear/macrophage, once a cytokine storm is formed, the immune system kills viruses and a large number of normal cells of the lung at the same time, the ventilation function of the lung is seriously damaged, the lung CT shows a large white color, namely white lung, and the patient can breathe and fail until the patient dies due to hypoxia. It is worth emphasizing that vascular endothelial cells, heart, kidney, liver, digestive tract and other tissues and organs in human body also highly express ACE2, and all tissues and organs expressing ACE2 can be battlefields of novel coronavirus and immune cells, and finally lead to multi-organ failure and life threatening.
Thus, treatment of new coronaviruses requires not only inhibition of viral replication in vivo, but also reversal of key cytokines that induce inflammatory storms, blocking of some of the monocyte/macrophage M1 polarization and its signaling, promotion of monocyte/macrophage M2 polarization, and reduction and repair of inflammatory response damage to the patient's lung tissues and multiple organs. The invention further uses an IL-6 inhibitor in combination with the 2019-nCoV3CL hydrolase (Mpro) inhibitor to inhibit excessive M1 polarization of macrophages in a patient, control the generation of inflammatory storm, promote M2 polarization of the macrophages and promote the repair of damaged tissues of a pneumonia patient.
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
2019-nCoV is also a Positive strand virus (Positive stranded RNA virus) like SARS-CoV which belongs to a coronary virus species related to severe acute respiratory syndrome, and the replication enzyme (Replicase) translates nucleotide (RNA) in the virus to form polyprotein (polyprotein), which mainly performs replication and transcription of the virus, but must be converted into polypeptides (polypeptide) with certain biochemical functions through protein solubilization, and the work is completed by hydrolysis protease (protease). Therefore, 3CL proteolytic enzyme (3 CL Mpro) is considered to be an ideal anti-SARS-CoV drug screening target. The corresponding enzyme is also considered to be a potential target of 2019-nCoV. Aiming at the high-resolution crystal structure of 2019-nCoV hydrolase (Mpro) of the new coronavirus which is obtained at present, the strategy of combining virtual screening and enzymatic test can be comprehensively utilized, and the existing molecular drugs are screened by combining four databases such as BindingDB, PubChem, ChEMBL and PDB, so that the small molecular drug inhibitor capable of inhibiting the Mpro is screened. In the invention, the following inhibitors are mainly screened out: indinavir, saquinavir, lopinavir, carfilzomib, ritonavir.
The pulmonary inflammatory imbalance and inflammatory injury are main reasons for high late stage death rate of new coronary patients, the macrophages are divided into proinflammatory-M1 type macrophages and anti-inflammatory-M2 type macrophages according to functions of the macrophages, the M1 type macrophages secrete proinflammatory factors to cause the pulmonary proinflammatory/anti-inflammatory imbalance, the M1 type macrophages secrete proinflammatory factors such as Interleukin (IL) -1, TNF α, IL-6, IL-8, IL-12 and iNOS, and the inflammatory factors act on the macrophages to activate more M1 type macrophages on one hand and interact with epithelial cells, lymphocytes and neutrophils to promote the progress of pulmonary inflammatory response on the other hand.
It is known that, after infection with a novel coronavirus, pathogenic T cells are rapidly activated to produce factors such as granulocyte-macrophage colony stimulating factors GM-CSF and IL-6. GM-CSF will further activate CD14+ CD16+ inflammatory monocytes, producing greater amounts of IL-6 and other inflammatory factors, thereby forming an inflammatory storm that results in severe immune damage to the lungs and other organs. Overexpression of IL-6, promoting polarization of macrophage M1 type, further exacerbates the proinflammatory/anti-inflammatory imbalance. Meanwhile, the expression of IL-6 in the lung can cause the lack of inducers and sensitizers of M2 type macrophages, the M2 type macrophages have insufficient polarization, the M2 type macrophages mainly play an anti-inflammatory effect and can play an anti-inflammatory effect through three ways, and the lack of the M2 type macrophages directly causes the insufficient anti-inflammatory effect of the lung.
Aiming at the problems, the invention utilizes Vero E6 cell-monocyte macrophage (Thp-1) co-culture inoculated with 2019-nCoV to establish an in vitro cell and inflammation model of the 2019-nCoV. The Vero E6 cells inoculated with 2019-nCoV can visually observe the inhibition effect on viruses through the survival condition of the Vero E6 cells, and Thp-1 serving as undifferentiated mononuclear macrophages can autonomously select M1 polarization to promote inflammation and resist virus invasion on one hand when stimulated by the viruses, and can select the polarization direction of the Thp-1 through external stimulation on the other hand, so that the Thp-1 is favorable for prognosis repair and avoids unnecessary damage caused by inflammatory storms. The method comprises the following specific steps: the polycarbonate membrane (PC) separates the upper and lower layers in a 24-well plate, wherein the upper layer is seeded with Thp-1 cells, and the lower layer is seeded with Vero E6 cells infected with 2019-nCoV, and the upper layer and the lower layer are separated by 0.4 mu m of PC, so that the cells between the upper layer and the lower layer can not freely pass through to generate contact, but cytokines can freely pass through to generate interaction to mutually influence, as shown in a figure 1 in particular.
Before modeling, a drug toxicity test needs to be carried out on a small-molecule drug inhibitor of Mpro screened from Vero E6 cells inoculated with 2019-nCoV, and the main process is as follows:
1. 100 μ L of cell suspension was prepared in a 96-well plate, and the plate was incubated at 37 ℃ with 5% CO2The incubator is pre-cultured for 24 hours to ensure that the wall is attached;
2. adding 10 μ L of the substance to be tested at different concentrations to the culture plate to give final concentrations of 0.1, 0.3, 1, 3, 10, 30, 100 ng/mL;
3. incubating the culture plate in an incubator for 24 h;
4. add 10mL of CCK8 solution to each well;
5. measuring absorbance at 450nm with enzyme readerCalculating cell viability, and determining the IC of each drug on the cells50And (4) concentration. The calculation formula is as follows:
cell viability [ (%) = [ a (medicated) -a (blank) ]/[ a (0 medicated) -a (blank) ] × 100
Wherein: a (adding medicine) is the absorbance of the medicine adding group after incubation for 24h, A (blank) is the absorbance of the medicine not added, and A (0 adding medicine) is the absorbance of the medicine adding group before incubation.
IC of 5 drugs50The values are as follows: indinavir: 3.21ng/mL saquinavir: 2.69 ng/mL lopinavir: 1.75 ng/mL carfilzomib: 4.42 ng/mL ritonavir: 4.58 ng/mL
In the co-culture model, three measures are required for upper layer macrophages, which are respectively: control group (without drug), IL-6 intervention group (with heavy human IL-6 at a drug concentration of 10. mu.g/mL), IL-6 inhibition group (with Tuzhuzumab at a drug concentration of 200. mu.g/mL). Vero E6 cells inoculated with 2019-nCoV at the lower layer need to take two measures: control group (without adding medicine), and medicine adding group (respectively adding the above 5 medicines, and adding IC with the concentration of the above different medicines50Value). The intervention measures of the upper layer of cells and the lower layer of cells are combined with each other, 6 groups of different experiments are finally needed to be carried out, and meanwhile, the experiment of different medicines is needed to be carried out in parallel aiming at the groups related to the medicines in the Vero E6 cells inoculated with 2019-nCoV at the lower layer. After the two cells are cultured for 48h, the upper layer cells are removed, the lower layer cells are subjected to cell viability measurement, and the cell viability under different intervention combinations (cell viability identification method and cytotoxicity test) is compared to verify the effect of the drug combination.
Finally, the activity of the Vero E6 cells is higher in the combination of the IL-6 inhibitor group than in the IL-6 treatment group and the control group, and the 5 Mpro-directed small-molecule inhibitors have certain protective effects on Vero E6 compared with the non-treatment group, wherein the effects of carfilzomib and saquinavir are obvious. Therefore, the combined administration of carfilzomib or saquinavir and IL-6 monoclonal antibody can be considered to have effective treatment on the new coronavirus and prognosis thereof. Therefore, the research result of the invention provides a new thought for the treatment research of the new coronavirus, and plays an important role in promoting the health cause of human beings.
Claims (3)
1.2019-nCoV3CL hydrolase inhibitor and interleukin-6 monoclonal antibody in preparing medicine for treating new coronary pneumonia.
2. Use according to claim 1, characterized in that: the 2019-nCoV3CL hydrolase inhibitor is selected from indinavir, saquinavir, lopinavir, carfilzomib or ritonavir.
3. Use according to claim 1, characterized in that: the 2019-nCoV3CL hydrolase inhibitor is carfilzomib or saquinavir.
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| CN112375737A (en) * | 2020-11-12 | 2021-02-19 | 常州市第一人民医院 | Biological adsorption material, preparation method, virus adsorption system and auxiliary dialysis circulation system |
| WO2021226174A1 (en) * | 2020-05-05 | 2021-11-11 | St. Jude Children's Research Hospital, Inc. | Methods for treating or reducing the severity of a viral infection |
| CN113667010A (en) * | 2020-05-15 | 2021-11-19 | 普米斯生物技术(珠海)有限公司 | Antibody of coronavirus and its derivative use |
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| WO2021226174A1 (en) * | 2020-05-05 | 2021-11-11 | St. Jude Children's Research Hospital, Inc. | Methods for treating or reducing the severity of a viral infection |
| CN113667010A (en) * | 2020-05-15 | 2021-11-19 | 普米斯生物技术(珠海)有限公司 | Antibody of coronavirus and its derivative use |
| CN113667010B (en) * | 2020-05-15 | 2023-07-28 | 普米斯生物技术(珠海)有限公司 | Antibody against coronavirus and use of derivative thereof |
| CN111870688A (en) * | 2020-07-09 | 2020-11-03 | 沣潮医药科技（上海）有限公司 | ACE2 protein and IL-6 or TNF alpha antagonist combination and application thereof |
| CN111870688B (en) * | 2020-07-09 | 2024-06-11 | 沣潮医药科技（上海）有限公司 | Combinations of ACE2 proteins with IL-6 or TNFa antagonists and uses thereof |
| CN113930481A (en) * | 2020-07-14 | 2022-01-14 | 中国科学院大连化学物理研究所 | Inhibitor screening kit for papain-like protease and application thereof |
| CN112375737A (en) * | 2020-11-12 | 2021-02-19 | 常州市第一人民医院 | Biological adsorption material, preparation method, virus adsorption system and auxiliary dialysis circulation system |
| CN112375737B (en) * | 2020-11-12 | 2023-03-28 | 常州市第一人民医院 | Biological adsorption material, preparation method, virus adsorption system and auxiliary dialysis circulation system |
| CN114848793A (en) * | 2021-02-05 | 2022-08-05 | 四川大学 | Use of polypeptides against coronaviruses |
| CN114848793B (en) * | 2021-02-05 | 2023-11-03 | 四川大学 | Use of polypeptides against coronaviruses |
| CN116355844A (en) * | 2023-05-31 | 2023-06-30 | 吉林大学第一医院 | Establishment and application of SARS-CoV-2 antigen induced cytokine storm model |
| CN116355844B (en) * | 2023-05-31 | 2023-08-18 | 吉林大学第一医院 | Establishment and application of SARS-CoV-2 antigen induced cytokine storm model |
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