CN115381800B - Selective agonist of liver X receptor and application thereof - Google Patents
Selective agonist of liver X receptor and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention belongs to the technical field of chemistry and medicine, and discloses a selective agonist of a liver X receptor and application thereof, wherein Petrosiol E is used as a selective agonist of the liver X receptor (Liver X Receptors, LXR), can act on ligand binding regions of LXR alpha and LXR beta, activates transcriptional activity of LXR alpha and LXR beta in a dose-dependent manner, selectively regulates and controls expression of target genes downstream of LXR alpha and LXR beta, and effectively avoids side effects such as fatty liver, hyperlipidemia and the like caused by non-selective LXR agonists. The petrosiol E provided by the invention is a selective LXR ligand with excellent properties, and has the activity of treating and improving diseases such as atherosclerosis, hyperlipidemia, alzheimer disease and the like.
Description
Technical Field
The invention belongs to the technical field of chemistry and medicine, and relates to a selective agonist of a liver X receptor and application thereof.
Background
Liver X receptors (Liver X Receptors, LXR) belong to the nuclear receptor superfamily and are ligand-dependent nuclear transcription factors, comprising two subtypes lxrα and lxrβ, which are widely expressed in a variety of tissue cell types in the body. Structurally, LXR consists of a ligand independent transcriptional activation region AF1 at the N-terminus, a DNA binding region (DNA binding domain, DBD) and a ligand binding region (ligand binding domain, LBD) at the C-terminus, a ligand dependent transcriptional activation region AF 2. LXR is a core regulator of cholesterol metabolism in body cells, and is closely related to the occurrence of various diseases, such as atherosclerosis, hyperlipidemia, alzheimer's disease, etc.
Atherosclerosis is a chronic inflammatory disease caused by lipid deposition on arterial vessel walls, foam cells formed by macrophages at the vessel walls due to accumulation and transformation of cholesterol are one of key factors for inducing atherosclerosis, and activating LXR in the macrophages can promote cholesterol efflux and inhibit inflammatory reaction so as to antagonize foam cell formation and atherosclerosis. In one aspect, activating LXR significantly upregulates expression of factors ABCA1, ABCG1, which regulate cholesterol efflux in macrophages, promotes cholesterol efflux in macrophages (venkateswanan, a. Et al Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc. Natl Acad. Sci. USA 97,12097-12102 (2000), kennedy, m.a. et al ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell metab.1,121-131 (2005)). On the other hand, activation of LXR can significantly inhibit macrophage inflammatory activation, and current studies have found that LXR can antagonize macrophage inflammatory activation through a variety of mechanisms, such as altering the components of membrane rafts to interfere with TLR signaling by ABCA1-dependent means (Ayaka Ito et al LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife (2015): 1-23).
The brain is also an active organ for cholesterol metabolism, and as a key regulator of cholesterol metabolism, the LXR has important regulation and control effects in the occurrence and development of nervous system degenerative diseases such as Alzheimer disease and the like. Microglial cells are taken as resident macrophages of a nervous system, play an important role in clearing damaged neurons, plaques and infection, and play an important role in regulating and controlling the occurrence and development of Alzheimer's disease. Recent studies have found that activation of microglial LXR significantly inhibits neuroinflammation inducing alzheimer's disease, enhances the ability of microglial cells to remove beta amyloid (nom Zelcer et al Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc. Natl Acad. Sci. USA 104,10601-10606 (2007)), improves microglial lipid metabolism disorders inducing neuronal damage, and suggests that activation of microglial LXR is an important pathway for effective prevention and treatment of alzheimer's disease (Ling Wang et al Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc. Natl Acad. Sci. USA99,13878-13883 (2002)).
The above description shows that activating LXR can promote cholesterol efflux of macrophages and microglia, inhibit inflammatory activation of macrophages and microglia, and improve occurrence and development of atherosclerosis, alzheimer disease and other diseases related to the inflammatory activation, so LXR is considered as an effective drug target for treating the related diseases. However, as research proceeds, it was found that activation of LXR induces several side effects while treating related diseases, such as activation of LXR enhances hepatic de novo fatty acid synthesis gene expression, inhibits hepatic cell Low Density Lipoprotein Receptor (LDLR) expression, thereby inducing side effects of fatty liver and hyperlipidemia (Zelcer, n., et al LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325,100-104 (2009), schultz, j.r., et al Role of LXRs in control of lipogenis. Genes dev.14,2831-2838 (2000)).
Ligands identified as having an activating LXR effect are now largely divided into two broad categories, one category being artificially synthesized ligand molecules and the other category being endogenous ligands in the organism. The synthetic ligands GW3965 and TO901317 have strong LXR activation and are commonly used tool compounds for activating LXR. Derivatives of oxidized cholesterol, intermediates in cholesterol synthesis, and some derivatives are endogenous ligands for LXR.
Based on the important biological regulation function of LXR, the development of therapeutic drugs with good therapeutic effect and small side effects by targeting LXR is always a research hot spot and a difficult point in the field. At present, the agonist drugs targeting the LXR have side effects of inducing fatty liver, blood lipid disturbance and the like because of non-selective activation of the LXR, and greatly limit the development of the drugs. Research in 2018 (Evan D. Muse et al. Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macro-gels. Proc. Natl Acad. Sci. USA 115, E4680-E4689 (2018)) has found that the endogenous ligand desmosterol is capable of Cell type-specific activation of LXR, specifically, selective activation of LXR and its downstream target gene expression in macrophages without affecting the expression of the LXR target gene associated with side effects in liver cells, thereby avoiding side effects associated with LXR activation. Therefore, searching for compounds with similar selective LXR agonistic activity is a new strategy for developing targeted LXR drugs with higher safety, effectively avoiding side effects.
Petrosiol E is a marine natural product, which the inventor group succeeded in synthesizing the compound for the first time in 2014 and obtained patent authorization (ZL 201410344864.5) for the compound synthesis method. At present, the research on the bioactivity of Petrosiol E at home and abroad is very limited, and only the research discovers that the Petrosiol E has the effect of promoting the differentiation of PC12 cell neurons. The result of the lack of targeted research on the molecular targets acting on Petrosiol E and their biological activities of regulating cholesterol metabolism and inhibiting inflammatory activation is unclear, which affects the further application of Petrosiol E function.
Disclosure of Invention
The invention aims at providing a drug or a drug component with potential therapeutic effect aiming at LXR targets.
The invention is realized by a selective agonist of liver X receptor and application thereof, wherein the selective agonist is Petrosiol E.
It is another object of the present invention to provide a selective LXR ligand for liver X receptor, which is petrosio E.
Another object of the present invention is to provide a use of the above selective agonist in the preparation of a medicament for treating or preventing a biological activity of regulating cholesterol metabolism and inhibiting inflammatory activation.
Another object of the present invention is to provide a use of the selective LXR ligand described above in the preparation of a medicament for treating or preventing biological activities of modulating cholesterol metabolism and inhibiting inflammatory activation.
Further, the biological activity of regulating cholesterol metabolism and inhibiting inflammatory activation is Alzheimer's disease.
Further, the biological activity of regulating cholesterol metabolism and inhibiting inflammatory activation is atherosclerosis.
In combination with the above technical solution and the technical problems to be solved, please analyze the following aspects to provide the following advantages and positive effects:
first, aiming at the technical problems in the prior art and the difficulty in solving the problems, the technical problems solved by the technical proposal of the invention are analyzed in detail and deeply by tightly combining the technical proposal to be protected, the results and data in the research and development process, and the like, and some technical effects brought after the problems are solved have creative technical effects. The specific description is as follows:
the natural product Petrosiol E dose-dependent activation nuclear receptors LXRalpha and LXRbeta can enhance the expression of macrophage and microglial LXR target genes ABCA1 and ABCG1, and has the equivalent effect of promoting the expression of ABCA1 and ABCG1 by endogenous selective ligand desmosterol; meanwhile, can obviously inhibit macrophage and microglial cell inflammation activation caused by lipopolysaccharide LPS; unlike the non-selective agonist of LXR GW3965, petrosiol E does not cause increased expression of target genes of side effects associated with LXR activation in human liver cells, petrosiol E dose-dependently inhibits lipid deposition in liver cells under conditions of exogenous lipid incubation; petrosiol E showed good therapeutic effect on the atherosclerosis and alzheimer's disease mouse model.
Secondly, the technical scheme is regarded as a whole or from the perspective of products, and the technical scheme to be protected has the following technical effects and advantages:
the Petrosiol E provided by the invention is a selective LXR agonist with novel structure type, selectively regulates and controls the expression of LXR downstream target genes, can effectively improve the occurrence and development of diseases such as atherosclerosis and Alzheimer's disease related to LXR activity, and simultaneously effectively relatively avoids side effects such as fatty liver and hyperlipidemia related to LXR activation.
The Petrosiol E provided by the invention is a selective LXR ligand with excellent properties, and has the activity of treating and improving diseases such as atherosclerosis, alzheimer disease and the like.
Drawings
FIG. 1 is a graph of the activity of Petrosiol E in promoting LXRalpha/beta transcription provided in the examples of the present invention;
FIG. 2 is a schematic representation of the Petrosiol E-promoted THP-1 macrophage LXR target gene ABCA1, ABCG1 expression pattern provided by the embodiment of the invention;
FIG. 3 is a schematic representation of the Petrosiol E-promoted BV-2 microglial LXR target gene ABCA1, ABCG1 expression provided by the example of the present invention;
FIG. 4 is a graph showing the inhibition of THP-1 macrophage inflammatory gene expression by Petrosiol E provided in the examples of the present invention;
FIG. 5 is a diagram showing the inhibition of BV-2 microglial inflammatory gene expression by Petrosiol E provided in the examples of the present invention;
FIG. 6 is a graph showing that Petrosiol E provided in the example of the present invention does not affect LXR target gene expression in hepatocytes;
FIG. 7 is a graph showing the effect of Petrosiol E on hepatocyte lipid deposition provided in the examples of the present invention;
FIG. 8 is a graph of Petrosiol E in accordance with an embodiment of the present invention inhibiting foam cell and atherosclerotic lipid plaque formation;
FIG. 9 shows a Petrosiol E modified ApoE provided by an embodiment of the present invention -/- A hyperlipoidemia map of the mice;
FIG. 10 is a graph of learning and memory capacity of the Petrosiol E modified SAMP8 fast-aging mice provided in the examples of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
An aim of embodiments of the present invention is to find a drug or pharmaceutical composition with potential therapeutic effects against LXR targets. Through extensive research, the inventors found that the natural product Petrosiol E dose-dependent activates the nuclear receptors lxrα and lxrβ; can enhance the expression of macrophage and microglial LXR target genes ABCA1 and ABCG1, and has the equivalent effect of promoting the expression of the ABCA1 by endogenous selective ligand desmosterol; meanwhile, can obviously inhibit macrophage and microglial cell inflammation activation caused by lipopolysaccharide LPS; significantly, unlike the non-selective LXR agonist GW3965, petrosiol E does not cause an increase in target gene expression associated with side effects such as fatty acid synthesis in human liver cells, and dose-dependent inhibition of lipid deposition in liver cells under conditions of exogenous lipid incubation; petrosiol E showed good therapeutic effect on the atherosclerosis and alzheimer's disease mouse model. The results show that the Petrosiol E is a selective LXR ligand with excellent properties and has the activity of treating and improving diseases such as atherosclerosis, hyperlipidemia, alzheimer disease and the like.
The technical scheme adopted by the embodiment of the invention is that a selective agonist and ligand of a liver X receptor and application thereof, petrosio E is used as a selective agonist of the liver X receptor (Liver X Receptors, LXR), and the structure is as follows:
the Petrosiol E can act on ligand binding regions of LXRalpha and LXRbeta, activates transcriptional activity of the LXRalpha and the LXRbeta in a dose-dependent manner, and effectively avoids side effects such as fatty liver, hyperlipidemia and the like caused by nonselective LXR agonists by selectively regulating and controlling expression of target genes downstream of the LXRalpha and the LXRbeta.
The Petrosiol E is used as a drug and a combination drug component for the treatment or prevention of biological activity that regulates cholesterol metabolism and inhibits inflammatory activation.
The following is a specific analytical description of the examples of the present invention in connection with the experimental procedure.
(1) Petrosiol E dose-dependent activation of nuclear receptors lxrα and lxrβ transcriptional activity.
As shown in FIG. 1, different concentrations of Petrosiol E were administered to Hek293 cells transfected with pCMX-Gal4-mLXR alpha-LBD or pCMX-Gal 4-mLXRbeta-LBD expression plasmid, tk-UAS-4 XLuc reporter plasmid and pRL-tk reference plasmid expressing the LXR ligand binding region by classical dual-luciferase reporter gene experiments for 24h incubation. The results indicate that the dose-dependent promotion of lxrα, lxrβ transcriptional activity of Petrosiol E suggests that Petrosiol E is able to bind to lxrα/β ligand binding domains and promote their transcriptional activation.
(2) Petrosiol E enhances macrophage and microglial lxrα/β target gene ABCA1, ABCG1 expression.
As shown in FIG. 2, human THP-1 monocytes underwent phorbol ester (PMA) induced differentiation for 48 hours to form THP-1 macrophages. THP-1 macrophages were given different concentrations (0.1,1,5, 10, 20, 30 μm) of Petrosiol E for 12 hours, RNA was extracted after the end of the treatment, and LXR regulated target gene ABCA1, ABCG1 expression was detected, indicating that Petrosiol E dose-dependent promotion of ABCA1, ABCG1 gene expression, the effect of which was comparable to that of the endogenous ligand Desmosterol.
As shown in fig. 3, microglial BV-2 was given different concentrations (0.1,1,5, 10, 20, 30 μm) of Petrosiol E for 12 hours, RNA was extracted after the end of the treatment, and LXR regulated target genes ABCA1, ABCG1 expression was detected, which indicated that Petrosiol E dose-dependent promotion of ABCA1, ABCG1 gene expression was comparable to endogenous ligand Desmosterol.
(3) Petrosiol E inhibits LXR down-regulated inflammatory gene expression in macrophages and microglia.
As shown in fig. 4, activation of LXR significantly inhibited inflammatory factor expression in macrophages, THP-1 macrophages were stimulated with lipopolysaccharide LPS and co-treated with different concentrations (0.1,1,5, 10, 20, 30 μm) of Petrosiol E, and RNA was extracted after the treatment was completed to detect inflammation-related target gene expression. The results show that the Petrosiol E dose-dependent inhibition of inflammatory genes IL-1 beta and TNF alpha expression in macrophages has a significantly stronger effect than Desmosterol and GW3965.
As shown in fig. 5, activation of LXR significantly inhibited inflammatory factor expression in macrophages, BV-2 microglia was stimulated with lipopolysaccharide LPS and co-processed with different concentrations (0.1,1,5, 10, 20, 30 μm) of Petrosiol E, RNA was extracted after the processing was completed, and expression of inflammation-associated target genes was detected. The results show that the Petrosiol E dose-dependent inhibition of inflammatory genes IL-1 beta and TNF alpha expression in macrophages has a significantly stronger effect than Desmosterol and GW3965.
(4) Petrosiol E does not affect target gene expression of LXR activation-related side effects in hepatocytes
As shown in fig. 6, activating LXR of liver cells causes a significant increase in fatty acid synthesis genes and thus induces side effects of liver steatosis. In the case of human hepatocytes L02 as a model, the administration of Petrosiol E, the selective ligand Desmosterol and the non-selective ligand GW3965 revealed that in hepatocytes, neither Petrosiol E nor Desmosterol caused an increase in the expression of LXR target gene-Fatty Acid Synthase (FASN), but GW3965 treatment significantly increased the expression of FASN.
As shown in fig. 7, human hepatocytes L02 were treated with different concentrations of Petrosil E and GW3965 for 24 hours, and after the treatment was completed, the lipid content of the cells was indicated by specific dye red O staining of the lipids, which indicated that the non-selective agonist GW3965 had an effect of promoting lipid accumulation, whereas Petrosil E was able to dose-dependently inhibit lipid accumulation of hepatocytes. The result shows that Petrosiol E can effectively avoid fatty liver side effects induced by LXR activation.
(5) Petrosiol E inhibits ApoE-/-mouse atherosclerotic plaque formation and improves hyperlipidemia.
As shown in fig. 8, male ApoE-/-atherosclerosis model mice were orally gavaged with 20mg/Kg Petrosiol E for 8 weeks, and after the treatment, the thoracic and abdominal aorta was removed and stained with oil red O (indicating atherosclerotic lipid plaque), and the oil red stained lipid plaque in the Petrosiol E treated group was significantly reduced compared to the control group, indicating that Petrosiol E inhibited foam cell formation and atherosclerosis plaque formation.
As shown in FIG. 9, male ApoE -/- The atherosclerosis model mice were fed with a high-fat diet and were orally and gastro-orally administered with 20mg/Kg Petrosiol E, and serum was collected after 8 weeks of continuous treatment to determine the blood lipid content. Compared with the control group, the content of the serum low density lipoprotein and the total cholesterol of the Petrosiol E treatment group is obviously reduced, which shows that the Petrosiol E can effectively improve the dyslipidemia.
(6) Petrosiol E improves learning and memory ability of SAMP8 alzheimer's disease mice
As shown in FIG. 10, male SAMP8 fast aging Alzheimer's disease mice were given 20mg/Kg of Petrosiol E treatment for 10 weeks, after the treatment was completed, the learning and memory ability of the mice was evaluated by open field test (open field test) and new object recognition test (Object recognition test), and the learning and memory ability of the Petrosiol E treated group was significantly improved as compared with the control group
The foregoing is merely illustrative of specific embodiments of the present invention, and the scope of the invention is not limited thereto, but any modifications, equivalents, improvements and alternatives falling within the spirit and principles of the present invention will be apparent to those skilled in the art within the scope of the present invention.
Claims (1)
1. Use of Petrosiol E for the preparation of a medicament for the treatment or prophylaxis of atherosclerosis and/or hyperlipidemia.
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