CN111925420B - Application of polypeptide as olfactory receptor Olfr109 agonist ligand - Google Patents

Application of polypeptide as olfactory receptor Olfr109 agonist ligand Download PDF

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CN111925420B
CN111925420B CN201911268458.4A CN201911268458A CN111925420B CN 111925420 B CN111925420 B CN 111925420B CN 201911268458 A CN201911268458 A CN 201911268458A CN 111925420 B CN111925420 B CN 111925420B
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olfr109
polypeptide
olfactory receptor
arrestin
beta
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CN111925420A (en
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于晓
孙金鹏
程杰
杨照
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Zhuhai Starcraft Biopharmaceutical Co ltd
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The disclosure particularly relates to an application of a polypeptide as an olfactory receptor Olfr109 ligand. Previous studies by the inventors found that the expression of Olfr109 in diabetes model mice is different from that of wild-type mice, suggesting that Olfr109 may be a target for metabolic diseases. The disclosure carries out further research and provides a ligand polypeptide of olfactory receptor Olfr109, a coding sequence and application thereof, wherein the ligand polypeptide of olfactory receptor Olfr109 can specifically bind to olfactory receptor Olfr109 and can effectively activate Olfr109 to generate a Gi, beta-arrestin-1 or beta-arrestin-2 signal channel. Based on the expression and the function of the Olfr109 in the pancreatic islet tissue, the ligand polypeptide obtained by the method can form the basis for developing the medicines for treating diabetes and obesity, and has good research and popularization significance.

Description

Application of polypeptide as olfactory receptor Olfr109 agonist ligand
Technical Field
The disclosure belongs to the technical field of anti-metabolic disease drugs, and particularly relates to application of a polypeptide serving as olfactory receptor Olfr109 agonist ligand and Gi, beta-arrestin-1 and beta-arrestin-2 signal channel agonists.
Background
The information in this background section is only for enhancement of understanding of the general background of the disclosure 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.
Olfactory receptor genes are the largest gene superfamily in vertebrates, and the encoded olfactory receptors belong to seven transmembrane G protein-coupled receptors. Mice have about 1000 functional olfactory receptors, while humans have about 350 functional olfactory receptors (Zhang and Firestein, 2002; Young, et al, 2002). The olfactory receptors are mainly distributed in olfactory epithelial cells in the nasal cavity, and enable the body to produce olfactory sensation and respond to external odor stimuli by recognizing and combining different odor molecules. Recent studies have shown that olfactory receptors are distributed in various tissues and organs of the body in addition to olfactory epithelial cells, and play a key role in regulating various physiological and pathological functions of the body, such as that the olfactory receptor MOR17-4 is expressed in sperm cells and regulates sperm motility and chemotaxis, while the olfactory receptor Olfr78 regulates renin secretion and blood pressure as a short-chain fatty acid receptor in the juxtaglomerular apparatus (Spehr, et al., 2003; Pluznick et al., 2013). In addition, the olfactory receptor OR1a1 regulates triglyceride metabolism in hepatocytes, suggesting that the olfactory receptor has an important role in the regulation of energy homeostasis in the body (Wu, et al, 2015).
The G protein-coupled receptor mediates an intracellular signal pathway by transmitting extracellular signals through G proteins and generating second messengers in cells upon receiving ligand stimulation, and inhibitory regulatory G proteins (Gi) are a class of G α proteins that are one of the subtypes of G proteins and can inhibit the activity of Adenylate Cyclase (AC), thereby reducing the level of cAMP. Currently, studies show that G protein-coupled receptors can interact with β -arrestins and perform signal transduction functions, such as activation of ERK, SRC, and other downstream signaling molecules.
Among them, the β -arrestin1 pathway was confirmed in CCK1R of British Journal of Pharmacology rather than being epilogue to mediate insulin secretion. Peltier's study also demonstrated that beta-arrestin-2 gene knock-out can lead to severe insulin resistance, and that beta-arrestin-2 mediates the formation of complexes containing IR/Akt/beta-arrestin-2/Src signals in the insulin signaling pathway, which play a critical role in the transmission of insulin signaling and the performance of insulin metabolic functions.
Disclosure of Invention
Previous studies by the inventors showed that there are expression profiles of multiple olfactory receptors on both mouse and human islets, where the expression level of Olfr109 in islets of model mice such as high sugar stimulated, L-arginine stimulated, and streptozotocin induced diabetes showed significant differences compared to wild mice, indicating that Olfr109 is a key factor in islet homeostasis and blood glucose maintenance. In view of the specific distribution and function, the Olfr109 has the potential to become a target for treating endocrine metabolic diseases such as diabetes and obesity. Therefore, the ligand which is effective and specifically binds to the Olfr109 is searched, a new tool can be provided for the functional research of the Olfr109, and a foundation is laid for the research and development of medicaments for treating endocrine metabolic diseases such as diabetes, obesity and the like which potentially target the Olfr 109.
The present disclosure provides the following technical solutions:
in a first aspect of the disclosure, a polypeptide is provided, which has an amino acid sequence as shown in SEQ ID NO. 1.
In a second aspect of the present disclosure, there is provided a gene sequence:
(1) for encoding the amino acid sequence shown as SEQ ID NO. 1;
(2) 1 for encoding the amino acid sequence shown in SEQ ID NO. 1, which is obtained by modifying, substituting, deleting or adding one or more amino acids;
preferably, the modification comprises amidation, phosphorylation, methylation, acetylation, ubiquitination, glycosylation or glycosylation.
In a third aspect of the present disclosure, there is provided an expression cassette comprising a gene sequence according to the second aspect.
In a fourth aspect of the present disclosure, there is provided a recombinant vector comprising the complete coding reading frame sequence of the expression cassette of the third aspect or the gene sequence of the second aspect.
Preferably, the vector is a plasmid or a viral vector.
Further preferably, the viral vector is a lentiviral vector, an adeno-associated viral vector or an adenoviral vector.
In a fifth aspect of the present disclosure, a kit is provided, which comprises the gene sequence of the second aspect, the expression cassette of the third aspect, or the recombinant vector of the fourth aspect.
In a sixth aspect of the disclosure, there is provided the use of Olfr109 as a target for modulation of Gi, β -arrestin-1 and β -arrestin-2 signal pathways.
In a seventh aspect of the disclosure, there is provided a use of a polypeptide of the first aspect as an Olfr109 agonist ligand.
In an eighth aspect of the present disclosure, there is provided a polypeptide of the first aspect, a gene of the second aspect, an expression cassette of the third aspect, or a recombinant vector of the fourth aspect for use as a Gi, β -arrestin-1 or β -arrestin-2 agonist.
Preferably, said use as an agonist comprises the use in the preparation of an anti-diabetic or anti-obesity medicament.
Compared with the prior art, the beneficial effect of this disclosure is:
1. the existing research provides the application of olfactory receptors OLFR734, OR1A1 and the like to the aspects of maintaining the glucose steady state of the body, reducing the blood fat and fat accumulation level, and provides a potential drug target for the treatment of diabetes and obesity. The research result of the disclosure reveals the relation between Olfr109 olfactory receptor and insulin receptor, further defines the relation between Olfr109 olfactory receptor and diabetes at the mechanism level, and provides more reliable basis for the application of olfactory receptor as the target for treating diabetes or obesity.
2. The disclosure provides a ligand sequence of Olfr109 olfactory receptor, which activates Gi, beta-arrestin-1 or beta-arrestin-2 through specific binding with Olfr109, provides a relatively clear regulation path and mechanism, and provides a corresponding guidance effect for the application of polypeptide in antidiabetic and obesity drugs.
Drawings
The accompanying drawings, which are included to provide a further understanding of the disclosure, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure and are not to limit the disclosure.
FIG. 1 is a graph showing the effect of the polypeptides of the examples on competitive binding to the olfactory receptor Olfr109 with a polypeptide labeled with radioactive I-125;
FIG. 2 is a graph showing the effect of the polypeptide of example 1 on binding to the olfactory receptor Olfr109 after being labeled with radioactive I-125;
FIG. 3 is a graph showing the effect of the polypeptide of example 1 on the activation of the Gi signaling pathway downstream of olfacto receptor Olfr 109;
FIG. 4 is a graph showing the effect of the polypeptide in example 1 on the activation of the beta-arrestin-1 signaling pathway downstream of olfactory receptor Olfr 109;
FIG. 5 shows the effect of the polypeptide of example 1 on the activation of the beta-arrestin-2 signaling pathway downstream of olfactory receptor Olfr 109.
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 disclosure 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 disclosure. 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.
As described in the background, olfactory receptors are distributed not only in the nasal cavity but also in various organs and tissues of the human body, and have a regulatory effect on various physiological and pathological functions of the human body. The inventor researches before to show that the expression of an olfactory receptor Olfr109 in a diabetes model mouse is different from that of a wild type, and the disclosure provides a section of polypeptide which can be used as a ligand of the olfactory receptor Olfr109, can effectively activate the Olfr109 to generate Gi and activate a beta-arrestin-1 or beta-arrestin-2 signal pathway, and is expected to have a treatment effect on metabolic diseases such as diabetes, obesity and the like.
In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific examples and comparative examples.
Example 1 the polypeptide specifically binds Olfr109 and activates the downstream signaling pathway of Olfr109
The experimental steps are as follows:
1. the following polypeptides were synthesized using a 431A peptide synthesizer (Perkin Elmer):
Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly
2. constructing gene recombinant Olfr109 recombinant plasmid by adopting a molecular biology method, overexpressing Olfr109 by using HEK293 cells, and competitively binding with an Olfr109 receptor by using a polypeptide labeled by a radioisotope I-125 and a non-labeled ligand, so as to detect the specific binding of the polypeptide and the Olfr109 receptor; specific binding of the polypeptide to Olfr109 receptor can be verified by binding of the polypeptide to Olfr109 receptor using a gradient concentration of the radioisotope I-125 labeled polypeptide.
3. The method uses HEK293 cells to over-express Olfr109, utilizes the principle that a Glosensor method can detect second messenger cAMP, stimulates cells to generate cAMP by Forskolin serving as an agonist of adenylate cyclase, and simultaneously gives polypeptide stimulation to represent the condition that the Olfr109 activates a Gi signal path according to the degree of causing the cAMP concentration in the cells to be reduced; the principle that the Olfr109 recruits the beta-arrestin-1 can be detected by utilizing a bioluminescence resonance energy transfer method of the Olfr109 and the beta-arrestin-1, and the condition that the Olfr109 activates a beta-arrestin-1 signal channel is represented by the efficiency of bioluminescence resonance energy transfer caused by polypeptide stimulation; the principle that the Olfr109 recruits the beta-arrestin-2 can be detected by utilizing the bioluminescence resonance energy transfer method of the Olfr109 and the beta-arrestin-2, and the condition that the Olfr109 activates a beta-arrestin-2 signal channel is represented by the efficiency of bioluminescence resonance energy transfer caused by polypeptide stimulation.
The polypeptide compound labeled by the radioactive isotope I-125 is prepared into working concentration of 0.2nM by PBS, and the non-labeled polypeptide compound is prepared into working concentration of 10 by PBS-12M、10-11M、10-10M、10-9M、10-8M、10-7M、10-6M、10-5M, in HEK293 cells overexpressing Olfr109, different concentrations (10) were given based on the stimulation with a polypeptide labelled with radioactive I-125-12-10-5M), incubating at 37 ℃ for 30 minutes, washing away unbound ligand polypeptide with buffer solution, collecting cells, detecting residual radioactivity by using a gamma counter, and performing statistical analysis and mapping on the result, wherein the result is shown in figure 1.
Radioisotope I-125 labeled polypeptide compounds were formulated with PBS to working concentrations of 0.01953125nM, 0.0390625nM, 0.078125nM, 0.15625nM, 0.3125nM, 0.625nM, 1.25nM, 2.5nM, non-labeled polypeptide compounds were formulated with PBS to working concentrations of 10 μ M, in HEK293 cells overexpressing Olfr109, pre-incubated with or without excess non-labeled polypeptide, stimulated with different concentrations (0nM-2.5nM) of radioactive I-125 labeled ligand polypeptide, incubated at 37 ℃ for 30 minutes at constant temperature, after washing away unbound ligand polypeptide, cells were harvested, residual radioactivity was detected using a gamma counter, pre-incubated sample with no excess non-labeled polypeptide as the total binding amount, pre-incubated sample with excess non-labeled polypeptide as the non-specific binding, and the results were plotted by statistical analysis, see FIG. 2.
The polypeptide compound to be detected is prepared into a working concentration of 10 by PBS-11M、10-10M、3*10-10M、10-9M、3*10- 9M、10-8M、10-7M, in HEK293 cells overexpressing Olfr109 and Glosensor, different concentrations (10. mu.M Forskolin stimulation was given on the basis of 10. mu.M Forskolin stimulation-11-10-7M), and the negative control is HEK293 cells expressing empty vector pcDNA and Glosensor, and a multifunctional microplate reader is used for recording fluorescence values in real time and performing statistical analysis and mapping on the result, wherein the result is shown in figure 3.
The polypeptide compound to be detected is prepared into a working concentration of 10 by PBS-9M、10-8M、3*10-8M、10-7M、3*10-7M、10-6M、10-5M, given at different concentrations (10) in HEK293 cells overexpressing Olfr109 and β -arrestin-1-9-10-5M), incubating for 10 minutes at constant temperature of 37 ℃, detecting a luminous value by using a multifunctional microplate reader, and carrying out statistical analysis and mapping on the result, wherein the result is shown in figure 4.
The polypeptide compound to be detected is prepared into a working concentration of 10 by PBS-9M、10-8M、3*10-8M、10-7M、3*10-7M、10-6M、10-5M, given at different concentrations (10) in HEK293 cells overexpressing Olfr109 and β -arrestin-2-9-10-5M) ligand polypeptide stimulation, incubation for 10 minutes at constant temperature of 37 ℃ and utilization of moreThe functional microplate reader detects the luminous value, and the results are plotted by statistical analysis, and are shown in figure 4.
The experimental result shows that the polypeptide compound can specifically bind to the olfactory receptor Olfr109, the half inhibitory concentration IC50 in a radioisotope ligand competitive binding experiment is 14.74nM, the polypeptide compound stimulates the olfactory receptor Olfr109 to generate Gi, beta-arrestin-1 and beta-arrestin-2 signal pathways, wherein the half effective concentration EC50 for activating the Gi signal pathway is 0.6nM, the half effective concentration EC50 for activating the beta-arrestin-1 signal pathway is 44nM, and the half effective concentration EC50 for activating the beta-arrestin-2 signal pathway is 36 nM.
The experimental results show that the polypeptide provided in the embodiment can target the Olfr109 to be a specific ligand thereof, and can effectively activate the Olfr109 to generate Gi, beta-arrestin-1 and beta-arrestin-2 signal pathways. Thus, the present disclosure provides promising compounds that may form the basis of drugs for intervention in endocrine-metabolic diseases such as obesity and diabetes.
The above description is only a preferred embodiment of the present disclosure and is not intended to limit the present disclosure, and various modifications and changes may be made to the present disclosure by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.
SEQUENCE LISTING
<110> Shandong university
<120> application of polypeptide as olfactory receptor Olfr109 agonist ligand
<130> 2010
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 15
<212> PRT
<213> Artificial sequence
<400> 1
Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly
1 5 10 15
<210> 2
<211> 45
<212> DNA
<213> Artificial sequence
<400> 2
tcccacctgg tggaggctct ctacctggtg tgtggggagc gtggc 45

Claims (1)

1. The application of a polypeptide as an Olfr109 agonist ligand is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1; the polypeptide can activate inhibitory regulatory G protein, beta-arrestin-1 or beta-arrestin-2 signal pathway; the use does not include diagnosis or treatment of disease.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1294597A (en) * 1998-02-23 2001-05-09 纽罗克里恩生物科学有限公司 Methods for treatment of diabetes using peptide analogues of insulin
US7018812B2 (en) * 2000-11-03 2006-03-28 Duke University Modified G-protein coupled receptors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1294597A (en) * 1998-02-23 2001-05-09 纽罗克里恩生物科学有限公司 Methods for treatment of diabetes using peptide analogues of insulin
US7018812B2 (en) * 2000-11-03 2006-03-28 Duke University Modified G-protein coupled receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Olfactory receptors：G protein-coupled receptor and beyond;Spehr M.等;《Journal of Neurochemistry》;20091231;1570-1583 *

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