CN114621125A - NLRP3 inflammasome inhibitor and application thereof - Google Patents
NLRP3 inflammasome inhibitor and application thereof Download PDFInfo
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- CN114621125A CN114621125A CN202011472140.0A CN202011472140A CN114621125A CN 114621125 A CN114621125 A CN 114621125A CN 202011472140 A CN202011472140 A CN 202011472140A CN 114621125 A CN114621125 A CN 114621125A
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Abstract
The invention relates to an NLRP3 inflammasome inhibitor and application thereof in preparing a medicament for preventing or treating NLRP3 inflammasome related diseases. The NLRP3 inflammasome inhibitor can specifically inhibit activation of NLRP3 inflammasome in vitro. The NLRP3 inflammasome inhibitor inhibits the interaction of NLRP3 and NEK7 by directly binding NLRP3, thereby inhibiting the assembly of inflammasome. The NLRP3 inflammasome inhibitors of the present invention are capable of treating a variety of NLRP3 inflammasome-related diseases in vivo, including DSS-induced colitis, HDM-induced allergic asthma, Experimental Allergic Encephalomyelitis (EAE), and high-fat food-induced obesity-related metabolic disorder syndrome.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to an NLRP3 inflammation corpuscle inhibitor and application thereof, in particular to application of the NLRP3 inflammation corpuscle inhibitor in preparation of a medicine for preventing or treating NLRP3 inflammation corpuscle related diseases.
Background
NLRP3(NACHT, LRR and PYD domains-binding protein3) inflammasome is a multimeric protein complex in cells, consisting of pattern recognition receptor NLRP3, adaptor protein ASC (immobilized specific-like protein binding a CARD) and caspase-1 precursor. As an important member of pattern recognition receptors, NLRP3 is capable of recognizing pathogen-related molecular patterns and risk-related molecular patterns derived from pathogens (e.g., bacteria, viruses, fungi), external environments (e.g., alum, asbestos), or hosts (e.g., cellular metabolites, cellular stress). After activation, NLRP3 can recruit adaptor protein ASC and caspase-1 precursor to form NLRP3 inflammasome. After the NLRP3 inflammasome is assembled, caspase-1 precursor is subjected to self-shearing to form caspase-1 with shearing activity, caspase-1 further causes shearing of IL-1 beta precursor and IL-18 precursor to form mature IL-1 beta and IL-18, so that immune response and inflammatory reaction are promoted, and immune homeostasis of an organism is maintained. Dysregulation of activation of NLRP3 inflammasome is closely related to the development of various diseases such as enteritis, multiple sclerosis, obesity, type II diabetes, metabolic syndrome, non-alcoholic fatty liver disease, alcoholic liver disease, nephropathy, behcet's disease, sepsis, gout, arthritis, viral inflammation such as viral hepatitis and pneumonia, acute and chronic tissue damage caused by infection, atherosclerosis, myocardial infarction, amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, depression, asbestosis, silicosis and silicosis, asthma or acute respiratory distress syndrome, peritonitis, uv-induced sunburn of the skin, contact hypersensitivity, familial cold autoinflammation syndrome, chronic infantile neurocutaneous joint syndrome, muckle-wecker syndrome and cold porphyrin related periodic syndrome (CAPS), and cytokine storm due to tumor therapy such as CART therapy and immune checkpoint inhibitor therapy, and the like. Therefore, NLRP3 inflammasome is an important target for the treatment of these diseases.
Several inhibitors of NLRP3 inflammasome have now been discovered, including exogenous small molecule compounds: MCC950, CY-09, etc.; natural extracts: rubescensine A, Tripterygium wilfordii, carotene, etc.; endogenous metabolites: beta-hydroxybutyric acid, prostaglandin E2, and the like. Some of the above inhibitors are capable of specifically targeting NLRP3 and have some therapeutic effects on NLRP3 inflammasome-related diseases, such as CY-09, but they also face lengthy drug efficacy assessments, safety assessments, and clinical testing for use in treating human diseases. Therefore, it is of great significance to find a small molecule drug which can target NLRP3, specifically inhibit activation of NLRP3 inflammasome, has a therapeutic effect on NLRP3 inflammasome-related diseases, and is closer to clinical application.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides an NLRP3 inflammasome inhibitor specifically targeting NLRP3 and application of the NLRP3 inflammasome inhibitor in preparing a medicament for preventing or treating NLRP3 inflammasome-related diseases.
In one aspect, the present invention provides NLRP3 inflammasome inhibitors having the structure shown by the formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group, and R is not a 3, 3-dinitro-1-azetidinyl group.
In another aspect, the invention provides a pharmaceutical composition comprising the NLRP3 inflammasome inhibitor and a pharmaceutically acceptable carrier. The pharmaceutical composition can be used for preventing or treating NLRP3 inflammasome related diseases.
In a further aspect, the invention provides the use of an NLRP3 inflammasome inhibitor for inhibiting in vitro activation of an NLRP3 inflammasome, the NLRP3 inflammasome inhibitor having the structure shown in the formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group.
In a further aspect, the invention provides the use of an NLRP3 inflammasome inhibitor for the manufacture of a medicament for the prevention or treatment of an NLRP3 inflammasome-related disease, said NLRP3 inflammasome inhibitor having the structure shown in the formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group.
In some embodiments, the 1-azacycloalkyl group is 1-azetidinyl, 1-azacyclopentyl, 1-azacyclohexyl; the arylamine group is phenylamino.
In some embodiments, R is further substituted with halo, alkyl, haloalkyl, alkoxy, acyl, nitro.
In some embodiments, the NLRP3 inflammasome-related disorders include inflammatory bowel disease, multiple sclerosis, obesity, type II diabetes, metabolic syndrome, nonalcoholic fatty liver disease, alcoholic liver disease, kidney disease, behcet's disease, sepsis, gout, arthritis, viral inflammation such as viral hepatitis and pneumonia, acute and chronic tissue damage caused by infection, atherosclerosis, myocardial infarction, amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, depression, asbestosis, silicosis and silicosis, asthma or acute respiratory distress syndrome, peritonitis, uv-induced sunburn of the skin, contact hypersensitivity, familial cold autoinflammation syndrome, chronic infantile neurocutaneous joint syndrome, muckle-wecker syndrome and cold porphyrin related periodic syndrome (CAPS), and cytokine storm due to tumor therapy such as CART therapy and immune checkpoint inhibitor therapy, and the like.
The above NLRP3 inflammasome-related diseases are preferably enteritis, asthma, autoimmune diseases, obesity, type II diabetes, fatty liver and atherosclerosis, and more preferably DSS (dextran sulfate sodium) induced colitis, HDM (House dust Mite) induced allergic asthma, EAE (experimental allergic encephalomyelitis) and high fat diet induced metabolic disorder symptoms with development of impaired glucose tolerance and hepatic steatosis and arterial vascular plaque formation.
The administration mode of the above-mentioned medicine is intraperitoneal injection, but is not limited thereto.
The dose for intraperitoneal injection is preferably 2.5mg/kg to 12mg/kg, the dose for enteritis, asthma and experimental allergic encephalomyelitis is preferably 8 mg/kg to 12mg/kg, such as 10mg/kg, and the dose for metabolic syndrome is preferably 2mg/kg to 3mg/kg, such as 2.5 mg/kg.
The inhibitor of NLRP3 inflammasome provided by the invention can specifically inhibit the activation of NLRP3 inflammasome in macrophage (BMDM) of bone marrow origin, and has no inhibiting effect on other inflammasome. The assembly of NLRP3 inflammasome is inhibited by inhibiting the interaction of NLRP3 and NEK7, thereby inhibiting the activation of NLRP3 inflammasome. Further, the NLRP3 inflammasome inhibitor is capable of directly binding to NLRP3 protein, thereby inhibiting the interaction of NLRP3 and NEK 7. More importantly, the NLRP3 inflammatory body inhibitor has good treatment effects on DSS-induced colitis, HDM-induced allergic asthma, Experimental Allergic Encephalomyelitis (EAE) and high fat food-induced obvious insulin resistance accompanied with the generation of impaired glucose tolerance and metabolic disorder symptoms such as hepatic steatosis, arterial vascular plaque formation and the like. Therefore, the invention provides the application of the NLRP3 inflammasome inhibitor in treating NLRP3 inflammasome related diseases and preparing medicaments for preventing or treating the related diseases.
Compared with the prior art, the invention discovers that the NLRP3 inflammasome inhibitor has excellent specific inhibitory activity on NLRP3 inflammasome. The NLRP3 inflammasome inhibitor can inhibit the occurrence and the development of enteritis, asthma, autoimmune diseases, obesity, type II diabetes, fatty liver and atherosclerosis. Therefore, the pharmaceutical composition has important significance for clinically treating NLRP3 inflammatory body related diseases (including enteritis, multiple sclerosis, obesity, type II diabetes, metabolic syndrome, nonalcoholic fatty liver disease, alcoholic liver disease, nephropathy, behcet disease, sepsis, gout, arthritis, viral inflammation such as viral hepatitis and pneumonia, acute and chronic tissue injury caused by infection, atherosclerosis, myocardial infarction, amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, depression, asbestosis, silicosis and silicosis, asthma or acute respiratory distress syndrome, peritonitis, ultraviolet-induced skin sunburn, contact hypersensitivity, familial cold type autoinflammatory syndrome, chronic infant neurocutaneous joint syndrome, Ware-Westh syndrome and cold porphyrin related periodic syndrome (CAPS), and tumor treatment such as cytokine storm caused by CAR-T therapy and immune checkpoint inhibitor therapy, and the like).
Drawings
FIG. 1 shows the effect of RRx-001 inhibiting Nigericin-induced activation of NLRP3 inflammasome in example 1 of the present invention; wherein, A shows the secretion of IL-1 beta, and B shows the cleavage of caspase-1 mature body and IL-1 beta mature body.
FIG. 2 shows the effect of RRx-001 inhibiting NLRP3 inflammasome agonist-induced activation of NLRP3 inflammasome in example 1 of the present invention; wherein, A shows the secretion of IL-1 beta, and B shows the cleavage of caspase-1 mature body and IL-1 beta mature body.
FIG. 3 shows the effect of RRx-001 in example 1 of the invention in inhibiting LPS-induced activation of non-classical NLRP3 inflammasome; wherein, A shows the secretion of IL-1 beta, and B shows the cleavage of the mature body of caSpase-1 and the mature body of IL-1 beta.
FIG. 4 shows the effect of RRx-001 in example 1 of the present invention on the Poly (dA: dT) -induced activation of AIM2 inflammasome and Salmonella typhimurium-induced activation of NLRC4 inflammasome; wherein A shows the secretion of IL-1. beta. and B shows the cleavage of caspase-1 mature bodies and IL-1. beta. mature bodies.
FIG. 5 shows the effect of RRx-001 in inhibiting the interaction of NLRP3 and NEK7 and inhibiting the assembly of NLRP3 inflammasome in example 1 of the present invention; where A is the oligomeric case of ASC, B is the case of the interaction of endogenous NLRP3 and NEK7, C is the case of the interaction of endogenous NLRP3 and ASC, and D is the case of the interaction of exogenous NLRP3 and NEK 7.
FIG. 6 shows the effect of RRx-001 binding directly to NLRP3 protein in example 1 of the invention; wherein, A is the case of RRx-001 binding to NLRP3 protein of BMDM cells, and B is the case of RRx-001 binding to NLRP3 protein over-expressed by 293T cells.
FIG. 7 shows the effect of RRx-001 in the treatment of DSS-induced colitis according to example 2 of the present invention; wherein, A is the change of the body weight of the mouse, B is the change of the disease activity index of enteritis of the mouse, C is the staining condition of colon sections of the mouse, D is a colon photo of the mouse, and E is the measurement statistical condition of the colon length of the mouse.
FIG. 8 shows the effect of RRx-001 in the treatment of HDM-induced allergic asthma in example 3 of the present invention; wherein A-E are the number of total cells, eosinophils, alveolar macrophages, neutrophils and lymphocytes in the mouse alveolar lavage fluid.
FIG. 9 shows the effect of RRx-001 in treating Experimental Allergic Encephalomyelitis (EAE) in example 4 of the present invention; wherein, A is the disease rating of EAE, B is the number of immune cells infiltrated by the central nervous system, C is the proportion of immune cells infiltrated by the central nervous system, D is the expression of inflammatory factors of the spinal cord, and E is the section staining of the spinal cord.
FIG. 10 shows the effect of RRx-001 in treating high fat food-induced obesity-related metabolic disorder syndrome in example 5 of the present invention; wherein, A is the change of the weight of the mouse, B is the change of the diet of the mouse, C is the random blood sugar change of the mouse, D is the fasting blood sugar change of the mouse, E is the result of the Glucose Tolerance Test (GTT) of the mouse, and F is the result of the insulin sensitivity test (ITT) of the mouse.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the present invention will be further described in detail with reference to the accompanying drawings in conjunction with the following specific embodiments.
In one embodiment of the invention, RRx-001 is used as an NLRP3 inflammasome inhibitor. RRx-001 is also called 1-bromoacetyl-3, 3-dinitroazetidine (ABDNAZ) with molecular formula C5H6BrN3O5The molecular structure is shown in the following formula.
RRx-001 is an anti-tumor medicament currently in phase III clinical trial, and research chaulmoogra RRx-001 has good treatment effect on cancers such as brain cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer and the like. RRx-001 can not only directly inhibit tumor cell proliferation, but also can be used as a chemosensitizer and a radiotherapy sensitizer to promote the sensitivity of chemotherapy and radiotherapy; RRx-001 can also promote polarization of immunosuppressive cells such as tumor associated macrophages (tumor associated macrophages) to an immunoactive direction, thereby treating tumors by immunotherapy. Mechanistically, RRx-001 is able to efficiently catalyze the production of Reactive Oxygen Species (ROS) and nitric oxide species (NO) in cells, alter intracellular redox balance, and also cause alterations in cellular epigenetics. RRx-001 is a compound with higher safety and fewer side effects, and has wide prospect in the aspect of preparing clinical medicines. At present, the role of RRx-001 in inflammatory diseases has not been reported.
Biological experiments
The experimental methods in the following examples are all conventional experimental methods unless otherwise specified. The test materials used in the following examples, unless otherwise specified, were purchased from a conventional biochemical reagent store, and are shown in Table 1.
Table 1: experimental material and experimental animal
Example 1 RRx-001 inhibits in vitro activation of macrophage NLRP3 inflammasome
First, RRx-001 inhibits Nigericin-induced IL-1 beta secretion
1. Differentiation of mouse bone marrow-derived macrophages (BMDMs): bone marrow of C57BL/6 mice of about 8 weeks old was collected, lysed for erythrocytes, and then differentiated for 4-5 days in DMEM medium (containing 10% fetal bovine serum and 25ng/ml M-CSF (macrophage colony stimulating molecule)).
2. Dividing the differentiated BMDM cells into 12-well plates, each well at 5X 105And (4) cells. The following day, cells were pretreated with opti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS) for 3 hours. Then, different concentrations of RRx-001(0nM, 100nM, 200nM, 300nM) were added for half an hour, and 5. mu.M Nigericin (Nigericin) was added to stimulate the cells for 15 minutes.
3. Cell supernatants and cell lysates were collected, and WB and ELISA were used to detect secretion of IL-1. beta. and p20, respectively, in the supernatants.
As shown in FIG. 1, RRx-001 dose-dependently inhibited nigericin-induced maturation and secretion of p20 and IL-1 β.
Second, RRx-001 inhibits multiple agonist activated inflammasome and non-classical inflammasome
Experiment one: RRx-001 inhibits multiple agonist activated inflammasome.
1. Dividing the differentiated BMDM cells into 12-well plates, each well at 5X 105The cells were pretreated with Opti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS) for 3 hours the following day. Then divided into two groups, the first group was added 300nM RRx-001 and the second group was added equal volumeThe first large group was subdivided into four groups, each group was stimulated with 5. mu.M Nigericin (Nigericin) for 15 minutes, 5mM ATP for 30 minutes, and 700ug/ml urate crystals (MSU) for 4 hours, and the last group was a negative control. The second major group was also divided into four groups, each of which was stimulated with 5. mu.M Nigericin (Nigericin) for 15 minutes, 5mM ATP for 30 minutes, and 700. mu.g/ml urate crystals (MSU) for 4 hours, and the last group was a negative control.
2. Cell supernatants and cell lysates were collected, WB and ELISA were used to detect secretion of IL-1 β and p20 in the supernatants, respectively.
As shown in figure 2, RRx-001 inhibits NLRP3 inflammasome agonist-induced activation of NLRP3 inflammasome.
Experiment two: RRx-001 inhibits activation of non-classical inflammasome.
1. Dividing the differentiated BMDM cells into 12-well plates, each well at 5X 105The next day, cells were pretreated with opti-MEM medium (containing 1% fetal bovine serum and 200ng/ml Pam3CSK4) for 3 hours. Then, different concentrations of RRx-001(0nM, 100nM, 200nM, 300nM) were added for half an hour, and cells were treated with 1. mu.g LPS using Lipo2000 transfection for 16 hours.
2. Cell supernatants and cell lysates were collected, and WB and ELISA were used to detect secretion of IL-1. beta. and p20, respectively, in the supernatants.
As shown in figure 3, RRx-001 dose-dependently inhibited non-classical inflammasome activation.
Thirdly, RRx-001 has no inhibiting effect on the AIM2 inflammasome activated by Poly (dA: dT) and the IPAF inflammasome activated by Salmonella typhimurium
1. Dividing the differentiated BMDM cells into 12-well plates, each well at 5X 105The cells were pretreated with opti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS) for 3 hours the following day. Then divided into two groups, the first group was treated with 300nM RRx-001 and the second group with equal volume of DMSO for half an hour, and the first group was divided into four groups, each group was stimulated with 5. mu.M Nigericin for 15 minutes, and transfected with 1. mu.g of poly (dA: dT)Cells were stimulated for 2 hours, stimulated with Salmonella typhimurium (Salmonella) for 4 hours, and the last group was negative control. The second major group was also divided into four groups, each of which was stimulated with 5. mu.M Nigericin (Nigericin) for 15 minutes, transfected with 1. mu.g of poly (dA: dT) for 2 hours, and stimulated with Salmonella typhimurium (Salmonella) for 4 hours, and the last group was a negative control.
2. Cell supernatants and cell lysates were collected, and WB and ELISA were used to detect the secretion of IL-1. beta. and p20 in the supernatants, respectively.
As shown in FIG. 4, RRx-001 specifically inhibited NLRP3 inflammasome activation without affecting poly (dA: dT) activated AIM2 inflammasome and Salmonella typhimurium (Salmonella) activated IPAF inflammasome.
Fourthly, RRx-001 inhibits ASC oligomerization and assembly of NLRP3 inflammasome complex
Experiment one: RRx-001 inhibits oligomerization of ASC.
Dividing the well differentiated BMDM cells into 6-well plates with 1 × 10 wells per well6The cells were pretreated with opti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS) for 3 hours the following day. Then, different concentrations of RRx-001(0nM, 100nM, 200nM, 300nM) were added for half an hour, and 3.5. mu.M Nigericin (Nigericin) was added to stimulate the cells for 15 minutes. Culture supernatants from each well were collected, protein was extracted, and WB tested for the inhibitory effect of RRx-001 on activation of NLRP3 inflammasome. Adding equal volume of NP-40 containing protease inhibitor into each well, performing ice lysis for 30 minutes, collecting lysate, centrifuging to remove supernatant, adding fresh cross-linking agent DSS with the final concentration of 2mM, performing room-temperature cross-linking for 30 minutes, washing precipitates twice with precooled PBS, centrifuging to remove supernatant, adding protein lysis buffer, heating at 100 ℃ for 10 minutes, and detecting ASC polymerization by WB.
As shown in fig. 5A, RRx-001 dose-dependently inhibited the oligomerization of ASC during NLRP3 inflammasome activation.
Experiment two: RRx-001 inhibits the interaction of endogenous NEK7 with NLRP3 and ASC and NLRP 3.
Dividing the well differentiated BMDM cells into 6-well plates with 1 × 10 wells per well6One cell, the next day, with oCells were pretreated for 3 hours with pti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS). Then, different concentrations of RRx-001(0nM, 100nM, 200nM, 300nM) were added for half an hour, and 3.5. mu.M Nigericin (Nigericin) was added to stimulate the cells for 15 minutes. Removing supernatant, adding equal volume of NP-40 containing protease inhibitor into each well, performing ice-bath lysis for 30 minutes, collecting lysate, centrifuging to obtain supernatant, using a part as cell lysate, detecting expression of NLRP3 and NEK7 or ASC by WB, adding Protein G-coated beads and antibodies of NEK7 or ASC into a part, performing rotary incubation at 4 ℃ for 2 hours, centrifuging, washing the beads by NP-40, centrifuging to remove supernatant, adding Protein lysis buffer, and detecting interaction of NLRP3 and NEK7 and interaction of NLRP3 and ASC by WB.
As shown in fig. 5B, 5C, RRx-001 inhibited the interaction of endogenous NLRP3 and NEK7, thereby inhibiting the assembly of NLRP3 inflamed bodies.
Experiment three: RRx-001 inhibits the interaction of exogenous NLRP3 with NEK 7.
The 293T cells are divided into 6-well plates, when the cell density reaches about 80%, FLAG-NEK7 and VSV-NLRP3 plasmids are transfected respectively or simultaneously, RRx-001(0 mu M, 1 mu M and 2 mu M) with different concentrations is added after 8 hours of transfection, and the culture is continued for 16 hours. Removing supernatant, adding equal volume of NP-40 containing protease inhibitor into each well, performing ice lysis for 30 minutes, collecting lysate, centrifuging to obtain supernatant, taking one part as cell lysate, detecting the expression condition of transfection plasmid by WB, adding beads coated with FLAG antibody into one part, performing rotary incubation at 4 ℃ for 2 hours, centrifuging, cleaning the beads by NP-40, centrifuging to remove supernatant, adding protein lysis buffer, and detecting the interaction of NLRP3 and NEK7 by WB.
As shown in FIG. 5D, RRx-001 was able to inhibit the interaction of exogenous NLRP3 and NEK 7.
Fifthly, RRx-001 and NLRP3 protein interact
Experiment one: RRx-001 interacts with NLRP3 protein of BMDM cells.
Differentiated BMDM cells were removed from the supernatant, replaced with Opti-MEM medium (containing 1% fetal bovine serum and 50ng/ml LPS), and treated for 3 hours. Removing supernatant, adding NP-40 containing protease inhibitor, cracking on ice for 30 min, collecting lysate, and centrifuging to obtain supernatant. The obtained cell lysates were divided into three groups, and different concentrations of RRx-001 (0. mu.M, 5. mu.M, 50. mu.M) were added thereto, followed by rotary incubation at 4 ℃ for 2 hours. Each large fraction was divided into two groups, and each group was incubated with 25 ng/. mu.g of pronase or an equal volume of water at room temperature for 20 minutes. Adding protein lysis buffer, WB detects degradation of NLRP3 inflammasome-related protein by pronase.
As shown in fig. 6A, RRx-001 was able to specifically interact with NLRP3 protein, and not with other components of NLRP3 inflammasome.
Experiment two: RRx-001 interacts with over-expressed NLRP3 protein.
The 293T cells are divided into 6-well plates, and after the cell density reaches about 80%, FLAG-NLRP3 plasmid is transfected. Then, the supernatant was removed, NP-40 containing a protease inhibitor was added, and the mixture was lysed on ice for 30 minutes, followed by collecting the lysate and centrifuging the lysate to obtain the supernatant. The cell lysates obtained were divided into two groups, 50. mu.M RRx-001 and an equal volume of DMSO were added, respectively, and incubated for 2 hours at 4 ℃ with rotation. Each large fraction was divided into two groups, each group was incubated with 10 ng/. mu.g protease pronase or an equal volume of water at room temperature for 20 minutes. Adding protein lysis buffer, WB detecting degradation of NLRP3 protein by pronase.
As shown in fig. 6B, RRx-001 is capable of interacting with an overexpressed NLRP3 protein.
In another example, a series of compounds similar in structure to RRx-001 were synthesized and found to have the same in vitro inhibitory effect on NLRP3 by the same experiments, and the results are shown in Table 2.
Table 2: NLRP3 inhibition of different compounds
Note: the inhibition rate was less than 10%, and the activity was considered as inactive.
Example 2 RRx-001 inhibits DSS-induced colitis
1. 20 male C57BL/6J mice at 8 weeks of age were divided into 4 groups of 5 mice each.
2. Each set of treatments was as follows:
the first group provides normal drinking water.
In the second group, water containing 3% DSS was provided by daily intraperitoneal injections of solvent (90% PBS and 10% DMSO) for 6 days before changing to normal water.
In the third group, 5mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) was intraperitoneally administered daily to provide 3% DSS-containing drinking water for 6 days and then replaced with normal drinking water.
In the fourth group, 10mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) was intraperitoneally administered daily to provide 3% DSS-containing drinking water for 6 days, followed by changing to normal drinking water.
3. Mice body weight and disease activity index were measured daily, mice sacrificed on day ten, colon length was measured, colon tissue sections were taken and HE stained.
As shown in figure 7, drinking water containing DSS obviously causes the weight of mice to be reduced, the disease activity index of enteritis is increased, colon is shortened, the infiltration of colon immune cells is increased, and the colon is seriously damaged. And the injection of RRx-001 can obviously inhibit the weight loss of mice, reduce disease activity index, inhibit colon shortening, inhibit the increase of infiltration of colon immune cells and improve colon injury. This suggests that RRx-001 is effective in inhibiting DSS-induced colitis.
Example 3 RRx-001 inhibition of HDM-induced allergic asthma
1. 10 male C57BL/6J mice at 8 weeks of age were divided into 2 groups of 5 mice each.
2. Each set of treatments was as follows:
a first group: asthma was induced by nasal HDM injections of Day0 and Day7-11, which were administered intraperitoneally at 10mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) every two days.
Second group: asthma was induced by nasal drops of HDM in Day0 and Day7-11, with an equal volume of solvent (90% PBS and 10% DMSO) intraperitoneally every two days.
3. Day14 sacrificed mice, alveolar lavage fluid was removed and the proportion and number of cells in the alveolar lavage fluid was analyzed by flow cytometry.
As shown in fig. 8, RRx-001 significantly inhibited HDM-induced allergic asthma.
Example 4 RRx-001 inhibits the development of EAE (Experimental allergic encephalomyelitis)
1. 10 male C57BL/6J mice at 8 weeks of age were divided into 2 groups of 5 mice each.
2. Each set of treatment was as follows:
a first group: the EAE was induced by subcutaneous MOG peptide injection by Day0, intravenous PTX injection by Day0 and Day2, intraperitoneal injection of 10mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) every two days.
Second group: the EAE was induced by subcutaneous injection of MOG peptide by Day0, intravenous PTX by Day0 and Day2, and intraperitoneal injection of equal volumes of solvent (90% PBS and 10% DMSO) every two days.
3. The mice were scored daily for EAE disease, Day22 sacrificed mice, spinal cord tissues were sectioned for staining, the proportion and number of immune cells infiltrating the central nervous system were analyzed by flow cytometry, and the expression of inflammatory cytokines in the spinal cord was analyzed by RT-qPCR.
As shown in FIG. 9, RRx-001 can significantly inhibit the occurrence and development of EAE, and inhibit the lesion and immune cell infiltration of the central nervous system of mice.
Example 5 RRx-001 treatment of obesity-related Metabolic disorder syndrome
1. 20 male C57BL/6J mice at 8 weeks of age were divided into 4 groups of 5 mice each.
2. Each set of treatments was as follows:
a first group: mice fed normal diet were injected intraperitoneally with solvent (90% PBS and 10% DMSO) daily.
Second group: mice fed normal diet were injected intraperitoneally with 2.5mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) daily.
Third group: mice after 12 weeks induction with high fat diet were fed with high fat diet continuously every day, and were injected intraperitoneally with a solvent (90% PBS and 10% DMSO) every day
And a fourth group: mice after 12 weeks of high fat diet induction were fed with high fat diet continuously daily by intraperitoneal injection of 2.5mg/kg of RRx-001 (dissolved in 90% PBS and 10% DMSO) daily.
3. Body weight was measured daily and mouse diet was recorded. After completion of the 8-week administration test, the body weight, random and fasting blood glucose of each group of mice were measured, respectively, and a Glucose Tolerance Test (GTT) and an insulin sensitivity test (ITT) were completed.
As shown in fig. 10, RRx-001 significantly improved impaired glucose tolerance and insulin resistance induced by high-fat diet, thereby inhibiting hyperglycemia. This suggests that RRx-001 enhances the body's sensitivity to insulin and glucose by balancing the body's inflammatory state, thereby inhibiting hyperglycemia and ameliorating metabolic disorders. Meanwhile, RRx-001 had no effect on mice on a normal diet.
As can be seen from the above examples, the compound RRx-001 provided by the invention has specific inhibition effect on NLRP3 inflammasome and a series of inflammatory diseases induced by the inflammasome,
the above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. An NLRP3 inflammasome inhibitor having the structure shown in formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group, and R is not a 3, 3-dinitro-1-azetidinyl group.
2. The NLRP3 inflammasome inhibitor according to claim 1, wherein the 1-azacycloalkane group is 1-azetidinyl, 1-azacyclopentyl, 1-azacyclohexyl; the arylamino is phenylamino; alternatively, R is further substituted with halogen, alkyl, haloalkyl, alkoxy, acyl, nitro.
3. A pharmaceutical composition comprising the NLRP3 inflammasome inhibitor of claim 1 or 2 and a pharmaceutically acceptable carrier.
4. Use of an NLRP3 inflammasome inhibitor for inhibiting in vitro activation of an NLRP3 inflammasome, the NLRP3 inflammasome inhibitor having the formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group.
5. Use according to claim 4, wherein the 1-azacycloalkane group is 1-azetidinyl, 1-azacyclopentyl, 1-azacyclohexyl; the arylamine group is phenylamino; alternatively, R is further substituted with halogen, alkyl, haloalkyl, alkoxy, acyl, nitro.
6. Use of an NLRP3 inflammasome inhibitor for the manufacture of a medicament for the prevention or treatment of an NLRP3 inflammasome-related disease, said NLRP3 inflammasome inhibitor having the structure shown in the formula:
wherein R is a substituted or unsubstituted 1-azacycloalkyl group, or a substituted or unsubstituted arylamine group.
7. Use according to claim 6, wherein the 1-azacycloalkane group is 1-azetidinyl, 1-azacyclopentyl, 1-azacyclohexyl; the arylamine group is phenylamino; alternatively, R is further substituted with halogen, alkyl, haloalkyl, alkoxy, acyl, nitro.
8. The use according to claim 6, the NLRP3 inflammasome related diseases comprise enteritis, multiple sclerosis, obesity, type II diabetes, metabolic syndrome, non-alcoholic fatty liver disease, alcoholic liver disease, kidney disease, behcet's disease, sepsis, gout, arthritis, viral inflammation such as viral hepatitis and pneumonia, acute and chronic tissue damage caused by infection, atherosclerosis, myocardial infarction, amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, depression, asbestosis, silicosis and silicosis, asthma or acute respiratory distress syndrome, peritonitis, uv-induced sunburn of the skin, contact hypersensitivity, familial cold autoinflammation syndrome, chronic infantile neurocutaneous joint syndrome, muckle-wecker syndrome and cold porphyrin related periodic syndrome (CAPS), and cytokine storm as a result of tumor therapy such as CART therapy and immune checkpoint inhibitor therapy.
9. Use according to claim 6, wherein the medicament is administered intraperitoneally, preferably at a dose of 2.5-12 mg/kg, wherein the dose for enteritis, asthma or experimental allergic encephalomyelitis is preferably 8-12mg/kg and the dose for metabolic syndrome is preferably 2-3 mg/kg.
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