CN115554403A - Application of steroid hormone DHEA as receptor ADGRG2 agonist ligand - Google Patents
Application of steroid hormone DHEA as receptor ADGRG2 agonist ligand Download PDFInfo
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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Abstract
The invention provides an application of steroid hormone DHEA as receptor ADGRG2 agonist ligand, belonging to the technical field of biological engineering and biological medicine. According to the invention, the research finds that the steroid hormone DHEA can be used as an endogenous ligand of an orphan receptor ADGRG2, so that the ADGRG2 is effectively activated to generate a Gs signal, and the steroid hormone DHEA can form the basis for developing a male reproductive system disease diagnosis and/or treatment drug, so that the steroid hormone DHEA has a good value in practical application.
Description
Technical Field
The invention belongs to the technical field of biological engineering and biomedicine, and particularly relates to application of steroid hormone DHEA as a receptor ADGRG2 agonist ligand.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
G protein-coupled receptors are the largest membrane receptor family and drug targets in the human genome, with about 30% of approved drugs acting by binding to GPCRs and modulating intracellular signaling. Among them, the adhesion-like G-protein coupled receptors (aggpcrs) are the second major family of GPCRs, with a total of 33 members. All aGPCRs have, in addition to the classical seven-transmembrane structure, some unique features, long N-termini with adhesive-like potential, which comprise an induced self-hydrolysable membrane-proximal domain (Hamann et al, 2015). Mutations in adhesion-like receptors are associated with many human diseases, such as adhesion-like receptors ADGRV1 and LPHN2/3, which are critical for cochlear hair cell survival and excitatory synapse formation, respectively, ADGRF5 mediates alveolar surfactant homeostasis via Gq signaling, ADGRG6 regulates skeletal development via downstream Gs signaling, and the like. The aGPCR family has great potential in drug discovery because it has been linked to a variety of different diseases and regulates many important physiological processes throughout the body.
ADGRG2 (adhesion-like G protein-coupled receptor G2), also known as GPR64 or human epididymal-specific protein 6 (HE 6), is highly expressed in the epididymis and efferent tubules of humans and mice, and has an important role in regulating male reproductive function. It has been reported in the literature that the knockout of ADGRG2 can lead to maladjustment of fluid reabsorption in the efferent tubules, resulting in male sterility (Davies et al, 2004). The well-known research further clarifies that ADGRG2 and Gq are co-located on the specific structural apical membrane of the output tubule with the help of beta-arrestin-1 and anion channel CFTR to form a regional signal transduction complex, and constitute rapid GPCR-ion channel coupling, thereby accurately regulating the chloride ion current of non-ciliated cells and the process of tubular reabsorption. Overexpression of ADGRG2 in vitro can cause Gs and Gq constitutive activity. However, endogenous ligands for ADGRG2 are not currently found.
Dehydroepiandrosterone (DHEA) is a naturally occurring C-19 adrenal steroid (5-androstane-3 β -ol-17-1) derived from cholesterol (Webb et al, 2006). Dehydroepiandrosterone is secreted mainly by the zona reticulis of the adrenal cortex in humans and other primates. The adrenal cortex secretes 75-90% of dehydroepiandrosterone per day, the remainder being produced by the testes and ovaries. DHEA 3 β -dehydroepiandrosterone sulfate (DHEA-S) is a hydrophilic storage form that circulates in the blood (baulie, 2002). DHEAS can be interconverted with dehydroepiandrosterone by dehydroepiandrosterone sulfotransferase and hydroxysteroid sulfatase (baulie, 2002). DHEA and DHEAs are the most abundant steroid hormones in humans, and are a potential androgen at higher blood concentrations than other steroids. DHEA is currently being used more and more in the treatment of In Vitro Fertilized (IVF) women with low ovarian function and has been reported to be effective in increasing pregnancy rates and embryo quality while decreasing miscarriage rates (Arlt et al, 1999 shohatt-tal et al 2015; poplar et al 2020 a). However, the physiological activity of DHEA remains to be studied further.
Disclosure of Invention
In view of the problems of the prior art, the present invention provides the use of the steroid hormone DHEA as a receptor ADGRG2 agonist ligand. According to the invention, the research finds that the steroid hormone DHEA can be used as an endogenous ligand of an orphan receptor ADGRG2, so that the ADGRG2 is effectively activated to generate a Gs signal, and the steroid hormone DHEA can form the basis for developing a male reproductive system disease diagnosis and/or treatment drug, so that the steroid hormone DHEA has a good value in practical application.
Specifically, the invention relates to the following technical scheme:
in a first aspect of the invention there is provided the use of an ADGRG2 modulating compound in the manufacture of a medicament for the diagnosis and/or treatment of a disease associated with the male reproductive system.
The male reproductive system related diseases include but are not limited to asthenospermia, necrospermia, epididymosis, spermatogenic dysfunction of testis and male infertility.
Wherein said ADGRG2 modulatory compound is a receptor ADGRG2 agonist or a receptor ADGRG2 inducible expression agent.
Further, the ADGRG2 agonist includes a ligand, polypeptide, antibody or small molecule compound that activates ADGRG 2.
The ligand comprises the steroid hormone DHEA.
In a second aspect of the invention, there is provided the use of dehydroepiandrosterone as a receptor ADGRG2 agonist ligand.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the above dehydroepiandrosterone or a solvate or pharmaceutically acceptable salt thereof.
And a pharmaceutical preparation comprising the dehydroepiandrosterone or a solvate thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant and/or carrier.
In a fourth aspect of the present invention, there is provided a use of the above DHEA or a solvate or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition or pharmaceutical preparation for preparing an ADGRG2 activator medicament or agent.
In a fifth aspect of the present invention, there is provided an application of the above DHEA or its solvate or its pharmaceutically acceptable salt, or the above pharmaceutical composition or pharmaceutical preparation in preparing a medicament or a reagent for treating a disease associated with abnormal expression of ADGRG 2.
In a sixth aspect of the invention, there is provided a method of treating a disease associated with aberrant expression of ADGRG2, comprising administering to a subject a therapeutically effective amount of DHEA or said pharmaceutical composition or pharmaceutical formulation.
The beneficial technical effects of one or more of the above technical solutions are as follows:
1. the existing research provides that the adhesion receptor ADGRG2 controls the reabsorption of the output tubule liquid of the male reproductive system and provides a potential drug target for the treatment of infertility. The research result of the technical scheme reveals the relationship of the adhesion receptor ADGRG2 and the male reproductive system diseases on a mechanism level, and provides a reliable basis for the application of the adhesion receptor as a male reproductive system disease treatment target.
2. The technical scheme provides the name and the compound structural formula of endogenous ligand steroid hormone of an adhesion receptor ADGRG2, provides a more definite regulation and control mechanism by specifically combining with the ADGRG2 and mediating a Gs signal path, provides a corresponding guidance function for the application of the steroid hormone in male reproductive system diseases, and has good practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are included to illustrate an exemplary embodiment of the invention and not to limit the invention.
FIG. 1 is a graph showing the effect of a steroid hormone DHEA-induced change in the extracellular configuration of the adhesion-type receptor ADGRG2 dose curve in example 1 of the present invention;
FIG. 2 is a graph showing the effect of the steroid hormone DHEA induced change in the configuration of the extracellular end of the adhesion receptor ADGRG2 in example 1 of the present invention;
FIG. 3 is a graph showing the effect of the steroid hormone DHEA on the Gs signaling pathway of the adhesion receptor ADGRG2 derived from mouse and human in example 1 of the present invention;
FIG. 4 is a graph of the increase in the output tubule primary cell CFTR current in wild type and ADGRG2 knockout mice mediated by the steroid hormone DHEA induced adhesion-like receptor, ADGRG2, in example 1 of the present invention.
FIG. 5 is a graph showing the increase in CFTR current in DHEA-induced HEK293 cells overexpressing the adhesion receptors ADGRG2 and CFTR or expressing CFTR alone in example 1 of the invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise. The experimental procedures, if specific conditions are not indicated in the following detailed description, are generally in accordance with conventional procedures and conditions of molecular biology within the skill of the art, which are fully explained in the literature. See, e.g., sambrook et al, molecular cloning: the techniques and conditions described in the laboratory Manual, or according to the manufacturer's recommendations.
As mentioned above, the adhesion receptor ADGRG2 has high specificity expression in the efferent tubule and epididymis, and has important regulation effect on the function of the male reproductive system. Previous research by the inventor shows that the adhesion receptor ADGRG2 is coupled with CFTR on mouse output tubule to regulate and control the reabsorption of the liquid in the tubule.
In view of the above, the present invention provides a steroid hormone DHEA, which can be used as an endogenous ligand of the adhesion receptor ADGRG2, can effectively activate ADGRG2 to generate Gs signals, and is expected to be a therapeutic drug for male reproductive system diseases.
In one embodiment of the invention, there is provided the use of an ADGRG2 modulatory compound in the manufacture of a medicament for the diagnosis and/or treatment of a disease associated with the male reproductive system.
In still another embodiment of the present invention, the diseases related to male reproductive system include, but are not limited to, asthenospermia, necrospermia, epididymal stasis, testicular spermatogenic dysfunction and male infertility.
In yet another embodiment of the invention, the ADGRG2 modulatory compound is a receptor ADGRG2 agonist or a receptor ADGRG2 inducible expression agent.
In yet another embodiment of the invention, the ADGRG2 agonist comprises a ligand, polypeptide, antibody or small molecule compound that activates ADGRG 2.
In yet another embodiment of the present invention, the ligand comprises the steroid hormone DHEA.
In yet another embodiment of the present invention, there is provided the use of dehydroepiandrosterone as a receptor ADGRG2 agonist ligand.
In another embodiment of the present invention, there is provided a pharmaceutical composition comprising the above dehydroepiandrosterone or a solvate or pharmaceutically acceptable salt thereof.
And a pharmaceutical preparation comprising the dehydroepiandrosterone or a solvate thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant and/or carrier.
The auxiliary material of the invention refers to the components of the pharmaceutical composition or the pharmaceutical preparation except the effective components, which are nontoxic to the testee. Adjuvants commonly used in the art such as buffers, stabilizers, preservatives or excipients, commonly used excipients such as binders, fillers, wetting agents, disintegrants and the like.
By way of example, optional excipients in the formulations of the present invention include, but are not limited to: the excipient is selected from calcium phosphate, magnesium stearate, talc, dextrin, starch, gelatin cellulose, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone.
The pharmaceutical carrier of the present invention may be a pharmaceutically acceptable solvent, suspension, vesicle, nanomaterial, etc., for delivery into the animal or human body. The carrier may be a liquid or solid and is selected according to the intended mode of administration, and the proteins and liposomes are also pharmaceutical carriers.
The compounds of the present invention may be formulated into pharmaceutical compositions or formulations using well known techniques by those skilled in the art. For example, the above-described DHEA of the present invention is mixed with a pharmaceutical excipient and then, if necessary, the resulting mixture is formed into a desired shape. And, in addition to those mentioned herein, suitable pharmaceutical excipients are known in the art, see for example the 2005 edition handbook of pharmaceutical excipients (fourth edition original), authors (english) r.c. lo (raymon dcrowe) (usa) p.j. susky (paul jsheskey).
In another embodiment of the present invention, there is provided a use of the aforementioned DHEA or a solvate thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition or pharmaceutical preparation for preparing an ADGRG2 activator medicament or agent.
In another embodiment of the present invention, there is provided a use of the above DHEA or a solvate or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition or pharmaceutical preparation for preparing a medicament or a reagent for treating a disease associated with abnormal expression of ADGRG 2.
In still another embodiment of the present invention, the diseases associated with abnormal expression of ADGRG2 include diseases associated with male reproductive system, further including but not limited to asthenospermia, necrospermia, epididymosis, spermatogenic dysfunction of testis, and male infertility.
In yet another embodiment of the present invention, there is provided a method for treating a disease associated with aberrant expression of ADGRG2, comprising administering to a subject a therapeutically effective amount of DHEA or said pharmaceutical composition or pharmaceutical formulation.
The subject of the present invention refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment, said subject being male (male).
A therapeutically effective amount according to the present invention is that amount of active compound or pharmaceutical agent, including a compound of the present invention, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other medical professional, which response includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
The range of therapeutically effective amounts that can be used will be known to the researcher, veterinarian, medical doctor or other medical professional in the art based on clinical trials or other means known in the art.
The diseases related to the abnormal expression of the ADGRG2 comprise diseases related to the male reproductive system, and further comprise, but are not limited to, asthenospermia, necrospermia, epididymosis, testicular spermatogenic dysfunction and male infertility.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1 experimental procedure for the specific binding of the steroid hormone DHEA to ADGRG2 and activation of the ADGRG2 downstream signaling pathway and modulation of ADGRG2 function in efferent tubules:
1. commercial steroid hormone DHEA was purchased from the alatin reagent official website.
2. A molecular biology method is adopted to construct a gene recombinant murine ADGRG2 recombinant plasmid, HEK293 cells are used for over-expressing murine ADGRG2, DHEA stimulation is given, the configuration change degree of the ADGRG2 induced by DHEA can be detected by using a bioluminescence resonance energy transfer method of an Nluc group at the N end of the ADGRG2 and a Flash group on an extracellular loop, and the specific combination of DHEA and ADGRG2 is reflected by the bioluminescence function energy transfer degree.
3. The activation of the Gs signaling pathway by ADGRG2 is characterized by the fact that HEK293 cells overexpress human or murine ADGRG2, the principle that a second messenger cAMP can be detected by a Glosensor method, and the intracellular cAMP concentration is detected by stimulating the cells with an agonist DHEA, so that the degree of increase of the intracellular cAMP concentration is caused.
4. Previous studies demonstrated that the adhesion-like receptor ADGRG2 and cystic fibrosis transmembrane conductance regulator (CFTR) co-localize at the apical membrane of efferent tubule non-ciliated cells, and ADGRG2 mediates the electrical current of CFTR. Wild mice and knock-out mouse output tubule single cells were isolated and infected with adenovirus ADGRG 2-promoter-RFP-labelled virus. Different concentrations of DHEA were given to stimulate primary cells and the current of ADGRG2-promoter-RFP-labeled cells was recorded by electrophysiological means.
HEK293 cells overexpress human or murine ADGRG2 and CFTR or separately overexpress CFTR, stimulated with different concentrations of DHEA, and whole cell currents of both cells were recorded by electrophysiological means.
DHEA was formulated with PBS to a working concentration of 10 -8 M、10 -7 M、10 -6 M、10 -5.5 M、10 -5 M、10 -4.5 M、10 -4 And M, incubating the cell over-expressing Nluc-ADGRG2-ECL1/2/3-Flash with a substrate Flash-EDT2 at a constant temperature of 37 ℃ for 40 minutes, washing the cell with PBS twice, stimulating with DHEA (dehydroepiandrosterone) with different concentrations, recording fluorescence values in real time by using a multifunctional microplate reader, and performing statistical analysis and mapping on the result, wherein the result is shown in figure 1.
DHEA was formulated with PBS to a working concentration of 10 -8 M、10 -7 M、10 -6 M、10 -5.5 M、10 -5 M、10 -4.5 M、10 -4 M, in HEK293 cells over-expressing human or mouse ADGRG2 and Glosensor, ligand stimulation with different concentrations is given, negative control is HEK293 cells expressing empty vector pcDNA and Glosensor, fluorescence values are recorded in real time by using a multifunctional enzyme labeling instrument, and the results are plotted by statistical analysis, and are shown in figure 2.
Wild mice and ADGRG2 full-body knockout mice were decapped and sacrificed, the output tubules were isolated, collagenase digested for half an hour and broken into single cells, infected with adenovirus ADGRG2-promoter-RFP-labeled virus, primary cells were digested after 48h onto 24mm × 24mm slides, after 12h primary cells were attached, the slides were mounted on the stage of a fluorescence microscope, stimulated with DHEA at different concentrations, primary cells that fluoresced red were selected and recorded for whole cell current with a HEKA EPC10 dual probe amplifier, the results are shown in FIG. 3 and FIG. 4.
Detecting DHEA-induced changes in CFTR current in vitro using HEK293 cells, formulating DHEA with PBS to a working concentration of 10 -8 M、10 -7 M、10 -6 M、10 -5.5 M、10 -5 M、10 -4.5 M、10 -4 M, in HEK293 cells co-expressing human or murine ADGRG2 with CFTR or overexpressing CFTR alone, with stimulation of different concentrations of ligand, whole cell currents were recorded using HEKA EPC10 dual probe amplifiers, and the results are shown in fig. 5.
The experimental result shows that DHEA can specifically bind to adhesion receptor ADGRG2, and the half effective concentration for inducing the change of extracellular loop ECL2 is 25uM; DHEA stimulates an adhesion receptor ADGRG2 to generate a Gs pathway, wherein the half effective concentrations of a human source and a mouse source are 11uM and 2uM respectively; DHEA can induce CFTR current increases in wild mouse and HEK293 cells co-expressing human or murine ADGRG2 and CFTR, with no effect on fully knockdown ADGRG2 mouse primary cells and HEK293 cells overexpressing CFTR alone, with the median effective concentration of DHEA-induced ADGRG 2-mediated CFTR current increase in primary cells being 14.2uM, and the median effective concentration of DHEA-induced human or murine ADGRG 2-mediated CFTR current increase in vitro overexpression systems being 19.6uM and 2.1uM, respectively.
The above experimental results show that the steroid compound DHEA provided in this example can target ADGRG2 to become its specific ligand, and can effectively activate ADGRG2 to generate Gs signaling pathway. Thus, the invention provides promising compounds which can form the basis of medicines for diagnosing and treating the male reproductive diseases.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
- Use of an adgrg2 modulatory compound in the manufacture of a medicament for the diagnosis and/or treatment of diseases associated with the male reproductive system;the ADGRG2 modulating compound is a receptor ADGRG2 agonist or a receptor ADGRG2 inducible expression agent.
- 2. The use according to claim 1, wherein the male reproductive system related disorders comprise asthenospermia, necrospermia, epididymal stasis, spermatogenic dysfunction of the testis, and male infertility.
- 3. The use of claim 1 wherein the ADGRG2 agonist comprises a ligand, polypeptide, antibody or small molecule compound that activates ADGRG 2;preferably, the ligand comprises the steroid hormone DHEA.
- 4. Use of dehydroepiandrosterone as a receptor ADGRG2 agonist ligand.
- 5. A pharmaceutical composition comprising dehydroepiandrosterone or a solvate or pharmaceutically acceptable salt thereof.
- 6. A pharmaceutical formulation comprising dehydroepiandrosterone or a solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier.
- 7. The pharmaceutical formulation of claim 6, wherein the adjuvant comprises a buffer, a stabilizer, a preservative, or an excipient.
- Use of dhea or a solvate or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 or a pharmaceutical formulation according to claim 7 or 8 in the manufacture of an ADGRG2 activator medicament or agent.
- Use of dhea or a solvate or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 or a pharmaceutical formulation according to claim 7 or 8 in the manufacture of a medicament or agent for a condition associated with aberrant expression of ADGRG 2;preferably, the diseases related to the abnormal expression of ADGRG2 include diseases related to the male reproductive system, and further include asthenospermia, necrospermia, epididymitis, testicular spermatogenic dysfunction and male infertility.
- 10. A method of treating a disease associated with aberrant expression of ADGRG2, comprising administering to a subject a therapeutically effective amount of DHEA or a pharmaceutical composition of claim 5 or a pharmaceutical formulation of claim 7 or 8.
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