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WO2016194788A1 - Procédé de sélection d'une substance permettant d'éliminer une odeur - Google Patents

Procédé de sélection d'une substance permettant d'éliminer une odeur Download PDF

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Publication number
WO2016194788A1
WO2016194788A1 PCT/JP2016/065656 JP2016065656W WO2016194788A1 WO 2016194788 A1 WO2016194788 A1 WO 2016194788A1 JP 2016065656 W JP2016065656 W JP 2016065656W WO 2016194788 A1 WO2016194788 A1 WO 2016194788A1
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Prior art keywords
odor
olfactory receptor
substance
target
receptor polypeptide
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English (en)
Japanese (ja)
Inventor
敬一 吉川
菜穂子 齋藤
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Kao Corp
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Kao Corp
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Priority claimed from JP2016096146A external-priority patent/JP6114439B2/ja
Application filed by Kao Corp filed Critical Kao Corp
Priority to EP16803223.3A priority Critical patent/EP3305898B1/fr
Priority to US15/576,514 priority patent/US10738101B2/en
Publication of WO2016194788A1 publication Critical patent/WO2016194788A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the present invention relates to a method for suppressing odor based on an odor adaptation mechanism.
  • odorous substances are recognized by olfactory receptors of olfactory neurons existing in the olfactory epithelium that spreads in the deepest part of the nasal cavity.
  • the odor molecules taken into the nasal cavity act on the olfactory receptor to activate it, and the signal from the olfactory nerve cell caused by the activated olfactory receptor is transmitted to the central nervous system. Is perceived.
  • sensory deodorization includes (1) the method of introducing other odorous substances into the malodorous environment and smelling them with the bad odor (masking), and (2) smelling other odorous substances before smelling the bad odor.
  • the method of sensory deodorization (2) is a method based on the physiological phenomenon of cross adaptation of olfaction.
  • the cross-adaptation of olfaction is defined as habituation to a different odor substance due to habituation to a certain odor substance and a decrease in olfactory sensitivity (Non-patent Document 3). That is, by getting used to odors that are not offensive odor, habituation occurs even for bad odors, and perception is suppressed.
  • Patent Document 2 an odor suppression method based on cross-adaptation that reduces the olfactory sensitivity to the odor-causing component by continuing to smell a substance that has a chemical structure that closely resembles the odor-causing component but has a weaker or unpleasant odor Is described.
  • Patent Document 3 describes a method for evaluating the odor similarity between a natural flavor and an imitation flavor simulating the odor based on cross adaptation. In Patent Document 3, assuming that two flavor compositions have the same odor, stronger cross adaptation occurs, and the effect of the adaptation appears in cerebral blood flow change. Evaluates the similarity of two flavors.
  • the decrease in odor sensitivity due to cross-adaptation can occur by various mechanisms such as olfactory receptor level, neural circuit level as well as olfactory receptor level.
  • Various hypotheses have been considered as the mechanism of olfactory cross-adaptation.
  • One is the hypothesis that cross-adaptation occurs in neurons in higher brain regions. In other words, it is a mechanism that loses sensitivity so that neurons in the higher brain region where information from peripheral olfactory neurons is integrated and odor quality is decoded do not continue to respond unnecessarily to odor information that remains unchanged .
  • Another is the hypothesis that cross-adaptation occurs at the level of olfactory receptors in peripheral olfactory neurons.
  • Non-patent Document 3 a substance causing cross-adaptation of a certain odor has a chemical structure very similar to that of the odor causing substance or a substance having a similar odor quality.
  • Non-Patent Document 4 it is reported that odor substances received by a single rat olfactory receptor have similar odor qualities, and these odor substances cause cross-adaptation in humans.
  • one odorant is recognized by many olfactory receptors with different selectivity.
  • Patent Literature 1 Japanese Patent No. 5646255 (Patent Literature 2) Japanese Patent Laid-Open No. 2005-53887 (Patent Literature 3) Japanese Patent No. 4966790 (Non-Patent Literature 1) Shirasu M. et al., Neuron, 81: 165 -178, 2014 (Non-Patent Document 2) venue JD et al., Nat.
  • Non-patent document 3 Kawasaki Michiaki and Horiuchi Tetsuro “Smell and smell substance” p71-72, Association of smell and smell, 1998 (Non-patent document 4) Pierce JD, Chemical senses, 21: 223-237 , 1996 (Non-Patent Document 5) Chemosensory Perception, 3 (3): 149-155, 2010
  • the present invention is a method for selecting a substance that causes cross-adaptation of a target odor, (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor;
  • a method comprising:
  • the present invention also provides a method for selecting a substance that suppresses the target odor, (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that suppresses the odor of the target;
  • a method comprising:
  • the present invention provides a method for selecting a substance that causes cross-adaptation of a target odor, (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor;
  • a method comprising:
  • the present invention is a method for selecting a substance that suppresses the odor of a target, (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that suppresses the target odor;
  • a method comprising:
  • Olfactory receptor response to muscone, guaiacol, p-cresol Olfactory receptor response to muscone, guaiacol, p-cresol.
  • the horizontal axis represents each of 370 olfactory receptors to be tested, and the vertical axis represents the relative response intensity of the receptors.
  • olfactory receptor OR1A1 Response of olfactory receptor OR1A1 expressing cells to various test substances.
  • the horizontal axis represents the test substance concentration, and the vertical axis represents the response intensity. Mock represents the response of cells that do not express olfactory receptors.
  • AB Responses of olfactory receptor OR10G4 (A) and OR9Q2 (B) expressing cells to various test substances.
  • the horizontal axis represents the test substance concentration, and the vertical axis represents the response intensity.
  • the bar represents the average value of the evaluation results of the sensory test, and the error bar represents standard error (SE).
  • olfactory receptor polypeptide refers to an olfactory receptor or a polypeptide having a function equivalent thereto
  • polypeptide having a function equivalent to an olfactory receptor refers to an olfactory receptor and Similarly, it can be expressed on the cell membrane, activated by the binding of odor molecules, and when activated, the amount of intracellular cAMP is activated by activating adenylate cyclase in combination with intracellular G ⁇ s or G ⁇ olf.
  • cent cross adaptation or olfactory cross adaptation relating to a target odor means that an odor of a substance other than the causative substance of the target odor is received in advance and used to the odor. It refers to a phenomenon in which the olfactory sensitivity to the causative agent of the target odor is reduced or changed.
  • smelling cross adaptation is a phenomenon based on olfactory receptor agonism.
  • an olfactory receptor for a target odor causative substance responds to a different odor causative substance prior to the response to the target odor causative substance, and then the response adapts, so that the target odor causative substance is later When exposed, only a low response is possible, resulting in a decrease or alteration in the intensity of the target odor recognized by the individual. Therefore, a substance that activates the response of the olfactory receptor to the causative substance of the target odor, such as an olfactory receptor agonist, can be used for the cross-adaptation of the target odor according to the present invention and the suppression of the target odor based on the target odor.
  • nucleotide sequence and amino acid sequence identity is calculated by the Lippman-Pearson method (Lipman-Pearson method; Science, 1985, 227: 1435-41). Specifically, using the homology analysis (Search homology) program of genetic information software Genetyx-Win (Ver. 5.1.1; software development), perform analysis with unit size to compare (ktup) as 2. Is calculated by
  • amino acid sequences and nucleotide sequences refers to 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and even more preferably It means 98% or more, preferably 99% or more identity.
  • the present invention provides a method for selecting a pair of odorants that cause cross-adaptation using an olfactory receptor response as an index.
  • the present invention also provides a method for selecting a substance that suppresses the odor based on cross-adaptation using the activation of an olfactory receptor for an odor-causing substance as an index.
  • a substance capable of selectively deodorizing a target odor based on cross adaptation can be efficiently selected.
  • the inventors of the present invention have suggested that there is a high relationship between odor perception and specific olfactory receptor response, such as musk fragrance and olfactory receptor OR5AN1, and guaiacol (2-methoxyphenol) and olfactory receptor OR10G4.
  • olfactory receptor response such as musk fragrance and olfactory receptor OR5AN1
  • guaiacol (2-methoxyphenol) and olfactory receptor OR10G4 By using a simple odor-olfactory receptor model, we succeeded in verifying the involvement of the olfactory receptor level in odor cross-adaptation for the first time.
  • the present inventors have discovered the principle that another substance recognized by an olfactory receptor that recognizes the target odor causing substance with high sensitivity causes cross-adaptation of the target odor.
  • the present inventors confirmed that the principle is universal as a result of further experiments with another odor-olfactory receptor model (p-cresol and OR9Q2). From the above, the present inventors have found that cross-adaptation can be examined for various odors by screening olfactory receptors for odor substance responsiveness and constructing a further odor-olfactory receptor model.
  • the present invention provides a method for screening or identifying a substance that causes cross-adaptation of a target odor and a substance that suppresses the target odor by cross-adaptation.
  • the present invention is a method for selecting a substance that causes cross-adaptation of a target odor, (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor;
  • a method comprising:
  • the present invention also provides a method for selecting a substance that suppresses the target odor, (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that suppresses the odor of the target;
  • a method comprising:
  • the present invention also provides a method for selecting a substance that causes cross-adaptation of a target odor, (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor;
  • a method comprising:
  • the present invention also provides a method for selecting a substance that suppresses the target odor, (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that suppresses the target odor;
  • a method comprising:
  • the above-described method of the present invention can be applied to all olfactory receptor polypeptides responsible for smell transmission and all odors recognized by them.
  • the method of the present invention may be a method performed in vitro or ex vivo.
  • a target odor to cause or suppress cross-adaptation
  • at least one olfactory receptor polypeptide having responsiveness to a causative substance of the target odor is prepared.
  • At least one olfactory receptor polypeptide that responds to a target odor-causing agent is searched for a group of olfactory receptor polypeptides from which the odor-causing agent is targeted. It can be obtained by identifying what responds.
  • the “olfactory receptor for the target odor causative agent” to be identified does not have to be all olfactory receptors capable of accepting the target odor causative agent, and is a receptor that plays a major role in the recognition of the target odor. Any receptor that can respond to the body, in other words, the causative substance of the target odor from a relatively low concentration, or exhibits a relatively high response to the causative substance of a certain concentration of odor may be used.
  • the dependence of the cellular response in which the receptor is expressed on the odor causative substance concentration is obtained, and the 50% effective concentration (EC50) calculated from the result is expressed as “an olfactory receptor for the causative substance of the target odor”. May be identified.
  • the “olfactory receptor for the target odor causative agent” to be identified is a receptor having a higher binding ability such as a low dissociation constant If it is.
  • an olfactory receptor polypeptide having responsiveness to a target odor causative substance is a response by various olfactory receptor polypeptides according to the method described in Reference Examples 1 and 2, as described in Example 1 described later. Can be identified by screening olfactory receptor polypeptides that respond to the causative agent of the target odor.
  • the olfactory receptor polypeptide used in the method of the present invention may be any mammal-derived olfactory receptor polypeptide.
  • mammal-derived olfactory receptor polypeptides include primates such as humans, chimpanzees, or olfactory receptor polypeptides derived from rodents such as mice and rats. And 400 or more olfactory receptors possessed by humans and polypeptides having functions equivalent thereto.
  • Information on human, mouse and rat olfactory receptors can be found in GenBank [www. ncbi. nlm. nih. gov].
  • the population of olfactory receptor polypeptides to be searched may be derived from a single mammalian species, or may contain olfactory receptor polypeptides derived from two or more different mammalian species. Good.
  • the population of olfactory receptor polypeptides to be searched is human, mouse and rat olfactory receptors, and at least 80% identical in amino acid sequence and having functions equivalent to those of olfactory receptors. More preferably, any of human olfactory receptors and polypeptides that are at least 80% identical in amino acid sequence to them and have functions equivalent to those of olfactory receptors including.
  • the olfactory receptor polypeptide can be used in any form as long as it does not lose responsiveness to the target odor causing substance.
  • the olfactory receptor polypeptide is a tissue or cell that naturally expresses the olfactory receptor polypeptide, such as an olfactory receptor or olfactory cell isolated from a living body, or a culture thereof; the olfactory receptor A membrane of an olfactory cell carrying a polypeptide; a recombinant cell genetically engineered to express the olfactory receptor polypeptide or a culture thereof; a membrane of the recombinant cell having the olfactory receptor polypeptide; It can be used in the form of an artificial lipid bilayer membrane having the olfactory receptor polypeptide. All of these forms fall within the scope of the olfactory receptor polypeptide used in the present invention.
  • the olfactory receptor polypeptide is a cell that naturally expresses the olfactory receptor polypeptide, such as a mammalian olfactory cell, or genetically engineered to express the olfactory receptor polypeptide. It can be a recombinant cell, or a culture thereof. Preferred examples include recombinant human cells that have been genetically engineered to express human olfactory receptor polypeptides.
  • the recombinant cell can be prepared by transforming a cell using a vector incorporating a gene encoding an olfactory receptor polypeptide.
  • the olfactory receptor polypeptide can also be expressed by directly introducing a gene transcription product into a cell.
  • a gene encoding RTP receptor-transporting protein
  • a gene encoding RTP1S is introduced into a cell together with a gene encoding the olfactory receptor polypeptide.
  • RTP1S includes human RTP1S. Human RTP1S is a protein registered in GenBank as GI: 50234917.
  • the type of target odor is not particularly limited, and generally known bad odors or unpleasant odors (for example, body odor, habit odor, halitosis, fecal odor, urine odor, tobacco odor, mold odor, dry odor, rot odor, garbage Odors, sewage odors, exhaust odors, duct odors, exhaust gas odors, etc.) as well as odors from foods or fragrance materials, odors from other substances (eg cosmetics, pharmaceuticals, cleaning agents, daily necessities, etc.), etc. Includes all the odors.
  • bad odors or unpleasant odors for example, body odor, habit odor, halitosis, fecal odor, urine odor, tobacco odor, mold odor, dry odor, rot odor, garbage Odors, sewage odors, exhaust odors, duct odors, exhaust gas odors, etc.
  • odors from foods or fragrance materials eg cosmetics, pharmaceuticals, cleaning agents
  • the causative substance of the target odor may be any substance that acts on the olfactory receptor to perceive the target odor.
  • the causative substance may be a naturally occurring substance, a substance artificially synthesized by a chemical or biological method, or a compound, a composition or a mixture. Also good.
  • the causative substance is a volatile substance.
  • causative agent examples include muscone, a causative agent of musk odor, guaiacol, a causative agent of tobacco odor, p-cresol, a causative agent of urine odor, 4-methyl-3- Hexenoic acid, 3-mercapto-3-methylhexanol, 3-hydroxy-3-methylhexanoic acid and 3-methyl-2-hexenoic acid, causative substances of odor, diosmine and 2-methyliso Borneol, skatole and indole that cause fecal odor or bad breath, nonanoic acid, hexanoic acid and isovaleric acid that cause body odor, volatile sulfur that is a cause of bad odor emitted from garbage, sewage or drainage Compounds, and butyl acrylate, pyrazine derivatives, furaneol, sotron and the like.
  • the causative substance of the target odor is added to the olfactory receptor polypeptide, and its response to the causative substance is measured.
  • the measurement may be performed by any method known in the art as a method for measuring the response of the olfactory receptor, for example, measurement of intracellular cAMP amount.
  • a method for measuring the response of the olfactory receptor for example, measurement of intracellular cAMP amount.
  • intracellular cAMP amount for example, when an olfactory receptor is activated by an odor molecule, it is known to increase the amount of intracellular cAMP by activating adenylate cyclase in combination with intracellular G ⁇ s. Therefore, the response of the olfactory receptor polypeptide to the causative substance can be measured by using the amount of intracellular cAMP after the causative substance is added as an index.
  • Examples of the method for measuring the amount of cAMP include an ELISA method and a reporter gene assay.
  • Another method for measuring the response of an olfactory receptor polypeptide includes a calcium imaging method.
  • Yet another method includes measurement by electrophysiological techniques. In electrophysiological measurement, for example, a cell (such as Xenopus oocyte) in which an olfactory receptor polypeptide is co-expressed with other ion channels is prepared, and the activity of the ion channel on the cell is measured by a patch clamp method, The response of the olfactory receptor polypeptide is measured by measurement using an electrode membrane potential fixation method or the like.
  • an olfactory receptor polypeptide that responds to the target odor-causing substance is identified. Evaluation of responsiveness can be performed by comparing the response of the olfactory receptor polypeptide (test group) to which the causative substance is added with the control group.
  • the control group includes the olfactory receptor polypeptide to which the causative substance at different concentrations was added, the olfactory receptor polypeptide to which the causative substance was not added, the olfactory receptor polypeptide to which a control substance was added, and the cause The olfactory receptor polypeptide before adding a substance, cells in which the olfactory receptor polypeptide is not expressed, and the like can be mentioned.
  • the control group includes other olfactory receptor polypeptides having no response or low response to the causative agent.
  • the olfactory receptor polypeptide is identified as responding to the target odor causative agent. For example, if the response of the olfactory receptor polypeptide in the test group is enhanced to 200% or more, more preferably 300% or more, and even more preferably 400% or more compared to the control group, the olfactory receptor is enhanced. Polypeptides are identified as responding to the target odor causative agent. Alternatively, if the response of the olfactory receptor polypeptide in the test group is statistically significantly enhanced as compared to the control group, the olfactory receptor polypeptide is responsive to the target odor causing substance. Identified as
  • the target odor causative substance may be added to the identified olfactory receptor polypeptide at a different concentration, and the response may be measured by the same procedure. If the response increases in a concentration-dependent manner of the causative agent, it can be confirmed that the olfactory receptor polypeptide is responsive to the causative agent of the target odor.
  • olfactory receptor polypeptides having responsiveness to a target odor causative agent When multiple types of olfactory receptor polypeptides having responsiveness to a target odor causative agent are found and their response intensities are different from each other, a relatively high responsiveness to the causative agent is shown among them 1
  • More than one species of olfactory receptor polypeptide can be further selected. For example, one, two, or three or more olfactory receptor polypeptides can be selected from the ones with the highest responsiveness to the target odor-causing substance, or the one with the highest responsiveness is selected. Can do. Alternatively, the olfactory receptor polypeptide having the lowest responsiveness to the target odor-causing substance can not be selected, or two or more of the responsiveness can be not selected.
  • the “selected” one or more olfactory receptor polypeptides are 200% or more, preferably 300% or more, more preferably 400, compared to each of the “non-selected” olfactory receptor polypeptides. % Responsiveness.
  • the sensitivity of the olfactory receptor polypeptide to the target odor causative substance can be evaluated using EC50, response threshold, etc. as an index, and a highly sensitive olfactory receptor polypeptide can be selected.
  • a highly sensitive and highly responsive olfactory receptor polypeptide can be selected based on the evaluation of responsiveness and response sensitivity.
  • Olfactory receptor polypeptides exhibit different basal activities depending on the type when expressed in cultured cells. Therefore, when comparing responses between olfactory receptor polypeptides, it is desirable to standardize the response values for each olfactory receptor polypeptide and compare the obtained normalized values between olfactory receptor polypeptides.
  • a standardization method for example, for a cell expressing one type of olfactory receptor, a relative value of a signal with respect to an odor stimulation when the signal value when no odor stimulation is performed is set to 1, 1 For example, a method of subtracting a signal value when no odor stimulation is performed from a signal value with respect to the odor stimulation for cells expressing various types of olfactory receptors.
  • an olfactory receptor polypeptide having responsiveness to the target odor-causing substance can be identified.
  • at least one olfactory receptor polypeptide that is responsive to the target odor-causing substance is prepared.
  • Examples of the at least one olfactory receptor polypeptide prepared in the method of the present invention include a human, mouse or rat olfactory receptor responsive to a causative agent of a target odor, and an amino acid sequence thereof. And at least one selected from the group consisting of polypeptides that are at least 80% identical and responsive to the target odor causative agent.
  • a human olfactory receptor that is responsive to a target odor causative agent, and at least 80% identical in amino acid sequence thereto, and responsive to the target odor causative agent include at least one selected from the group consisting of polypeptides.
  • Further preferred examples include a group of human olfactory receptors that are responsive to a target odor-causing substance, the olfactory receptors having the highest responsiveness, and at least 80% identical in amino acid sequence, and examples thereof include at least one selected from the group consisting of polypeptides having responsiveness to a target odor causing substance.
  • the most sensitive and highly responsive olfactory receptor and the amino acid sequence thereof are at least 80% identical.
  • the olfactory receptor polypeptide prepared in the method of the present invention may be at least one responsive to the target odor causative substance, or any two or more of them may be combined.
  • the target odor is a musk fragrance
  • the odor-causing substance is a musk fragrance
  • the olfactory receptor polypeptide used is represented by OR5AN1 (SEQ ID NO: 2) and SEQ ID NO: 2. And at least one selected from the group consisting of polypeptides having a responsiveness to musk fragrances (see FIG. 1).
  • the target odor is guaiacol (2-methoxyphenol)
  • the odor-causing substance is guaiacol
  • the olfactory receptor polypeptide used is OR10G4 (SEQ ID NO: 4)
  • Guaiacol is known to be a main causative substance of tobacco odor (Japanese Patent Laid-Open No. 2006-321944). Therefore, in one embodiment of the method of the present invention, the target odor is tobacco odor, and the olfactory receptor polypeptide used is represented by OR10G4 (SEQ ID NO: 4), which is a receptor for guaiacol, and SEQ ID NO: 4. And at least one selected from the group consisting of polypeptides that are responsive to tobacco odor-causing substances, preferably guaiacol.
  • the target odor is urine odor.
  • JP-A-2009-132770 discloses that p-cresol is the component that has the highest contribution to urine odor emitted from scattered and dried urine or diapers left after use, and p-cresol and other carbon numbers. It is described that a urine odor can be reproduced by a composition with 6 to 10 phenolic compounds.
  • International Publication No. 2009/037861 describes that when ⁇ -glucuronidase produced by bacteria acts on urine, p-cresol or other components increase in the urine, and the urine odor intensity is significantly increased. ing.
  • examples of the “urine odor-causing substance” in the present invention include urinary ⁇ -glucuronidase-treated product or an extract thereof, and p-cresol.
  • examples of the urinary ⁇ -glucuronidase-treated product include those obtained by adding ⁇ -glucuronidase to urine and urine on which ⁇ -glucuronidase produced by bacteria in the urine acts. These urine processed products or extracts thereof contain p-cresol.
  • OR9Q2 has been found as an olfactory receptor that recognizes p-cresol, which is a urinary odor causative substance (see FIGS. 1 and 2).
  • OR9Q2 is a polypeptide consisting of the amino acid sequence represented by SEQ ID NO: 6, which is registered as GI: 284413710 with GenBank. Therefore, preferably, when the target odor is urine odor in the method of the present invention, the olfactory receptor polypeptide used is at least 80% identical to OR9Q2 (SEQ ID NO: 6) and the amino acid sequence represented by SEQ ID NO: 6. It is at least one selected from the group consisting of an amino acid sequence and a polypeptide having responsiveness to a substance that causes urine odor, preferably p-cresol.
  • a test substance is added to the olfactory receptor polypeptide having responsiveness to the target odor-causing substance.
  • the test substance used in the method of the present invention is not particularly limited as long as it is a substance that is desired to be used as a substance that causes cross-adaptation of the target odor or as a substance that suppresses the target odor.
  • the test substance may be a naturally occurring substance, a substance artificially synthesized by a chemical or biological method, etc., or may be a compound, a composition or a mixture. Good.
  • the test substance is different from the causative substance of the target odor.
  • the test substance is a volatile substance and has a smell different from the target odor.
  • the test substance is a fragrance having an odor different from the target odor.
  • the response of the olfactory receptor polypeptide to the test substance is measured.
  • the measurement may be performed according to the method described above with respect to the measurement of the response of the olfactory receptor polypeptide to the causative agent of the target odor.
  • the receptor activation effect of the test substance is evaluated, and the test substance causing cross adaptation of the target odor is identified.
  • the effect of the test substance can be evaluated by comparing the response of the olfactory receptor (test group) to which the test substance is added with the control group.
  • test group As a control group, the olfactory receptor polypeptide to which the test substance of different concentration was added, the olfactory receptor polypeptide to which the test substance was not added, the olfactory receptor polypeptide to which the control substance was added, and the test substance were added.
  • the olfactory receptor polypeptide before the treatment, cells not expressing the olfactory receptor polypeptide, and the like can be mentioned.
  • the control group includes other olfactory receptor polypeptides that have no response or low response to the test substance.
  • the test substance can be evaluated as a substance that activates the response of the olfactory receptor polypeptide.
  • the effect of the test substance on the response of the olfactory receptor polypeptide is between the test substance addition group and the non-addition group, between the test substance addition group and the control substance addition group, before and after the addition of the test substance, or It can be evaluated by comparing the response of the olfactory receptor polypeptide between the olfactory receptor polypeptide-expressing cell group and the non-expressing cell group.
  • test substance When the response of the olfactory receptor polypeptide is induced by addition of a test substance, the test substance is evaluated as a substance that activates the response of the olfactory receptor polypeptide in response to the causative substance of the target odor.
  • the test is performed.
  • a substance can be evaluated as a substance that activates the response of an olfactory receptor polypeptide.
  • the response of the olfactory receptor polypeptide in the test substance-added group is statistically significantly enhanced as compared with the control group, the test substance activates the response of the olfactory receptor polypeptide. It can be evaluated as a substance.
  • the test substance that activates the response of the olfactory receptor polypeptide in response to the target odor-causing substance obtained above is selected as a substance that causes cross-adaptation of the target odor. That is, in the presence of the test substance, the olfactory receptor that recognizes the target odor is activated and subsequently responsiveness decreases due to adaptation, so that the responsiveness to the target odor causing substance added later is impaired. As a result, cross-adaptation of the target odor is caused by the test substance.
  • the test substance that activates the response of the olfactory receptor polypeptide that responds to the target odor causative substance obtained above is selected as a substance that suppresses the target odor. That is, the test substance is a substance that can suppress the target odor by causing cross adaptation of the target odor.
  • the test substance selected in the above procedure may be subjected to a sensory test to further evaluate its cross-adaptation ability or target odor suppression ability.
  • the sensory test can be performed in accordance with a deodorant evaluation procedure normally performed in the field, but preferably, the test substance and target for the evaluator are considered in consideration of the test substance being a cross-adaptation inducer.
  • the order of application of odor-causing substances is adjusted.
  • the evaluator first smells the candidate test substance selected in the above procedure and adapts to the smell.
  • the evaluator then smells the target and evaluates its intensity.
  • the evaluation results obtained are compared with the intensity of the target odor when not adapted to the test substance.
  • the test substance evaluated as having reduced the intensity of the target odor is selected as a substance that causes cross adaptation to the target odor or a substance that suppresses the target odor.
  • the substance selected by the method of the present invention is a substance that can suppress the target odor based on cross adaptation.
  • One embodiment of using a substance that suppresses the target odor obtained by the method of the present invention is as follows: First, the target is targeted to a subject who desires suppression of the target odor. Before being exposed to the odor of the target, the odor of the substance that suppresses the target odor is smelled. Alternatively, a substance that suppresses the odor of the target is applied to the subject so that the odor is stronger than the odor of the target. As a result, even if the subject is exposed to the target odor, the odor sensitivity to the target odor is reduced, and therefore the target odor is felt weak or no longer felt.
  • Examples of the application of the substance that suppresses the target odor obtained in the present invention include placing the substance in front of or in a toilet; carrying the substance to a person involved in excretion treatment in a ward or a nursing facility Or a method of exposing the substance before the treatment; a paper diaper or a sanitary product containing the substance; an undergarment, underwear, linen or other clothing containing the substance, a cloth product, or a fabric; Laundry detergents or softeners containing substances; cosmetics, detergents, deodorants and other external preparations containing the substances, pharmaceuticals, foods, etc .; production lines for products with a target odor or target odors generated Examples include, but are not limited to, application to the environment.
  • a method for selecting a substance that causes cross-adaptation of a target odor (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor; Including the method.
  • a method for selecting a substance that suppresses a target odor (1) searching for olfactory receptor polypeptides and identifying those that respond to the target odor causative agent; (2) adding a test substance to the identified olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of the olfactory receptor polypeptide as a substance that suppresses the odor of the target; Including the method.
  • the olfactory receptor polypeptide searched in (1) above is at least 80% identical in amino acid sequence to human, mouse and rat olfactory receptors and equivalent to the olfactory receptors ⁇ 1> or ⁇ 2>
  • a method for selecting a substance that causes cross-adaptation of a target odor (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that causes cross-adaptation of the target odor; Including the method.
  • a method for selecting a substance that suppresses a target odor (1) providing at least one olfactory receptor polypeptide responsive to a target odor causative agent; (2) adding a test substance to the at least one olfactory receptor polypeptide and measuring the response; (3) selecting the test substance that has activated the response of any of the at least one olfactory receptor polypeptide as a substance that suppresses the target odor; Including the method.
  • the at least one olfactory receptor polypeptide is preferably at least one selected from the group consisting of: Rat or mouse olfactory receptor; Human olfactory receptor; and 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more, even more preferably 98% or more in amino acid sequence with the rat, mouse or human olfactory receptor More preferably, the polypeptide is 99% or more identical and responsive to the target odor-causing substance.
  • the olfactory receptor polypeptide is expressed on a recombinant cell genetically engineered to express the olfactory receptor polypeptide, any of ⁇ 1> to ⁇ 6> The method according to claim 1.
  • the response of the olfactory receptor polypeptide is measured by intracellular cAMP amount measurement by ELISA or reporter gene assay, or by calcium imaging or electrophysiological technique, any one of ⁇ 1> to ⁇ 7> The method according to claim 1.
  • ⁇ 9> Preferably, (4) a substance that causes cross adaptation to the target odor or a substance that suppresses the target odor among the substances selected in (3) above by a sensory test.
  • a substance that causes cross adaptation to the target odor or a substance that suppresses the target odor among the substances selected in (3) above by a sensory test Preferably, (4) a substance that causes cross adaptation to the target odor or a substance that suppresses the target odor among the substances selected in (3) above by a sensory test.
  • ⁇ 10> The method according to any one of ⁇ 1> to ⁇ 9>, wherein the target odor is preferably a tobacco odor or a urine odor.
  • the method according to any one of ⁇ 4> to ⁇ 9> preferably,
  • the target odor is tobacco odor
  • the at least one olfactory receptor polypeptide is: A polypeptide comprising the amino acid sequence represented by SEQ ID NO: 4; and 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more, and even more preferably, with the amino acid sequence represented by SEQ ID NO: 4 Is a polypeptide that is 98% or more, preferably 99% or more identical and responsive to tobacco odor-causing substances,
  • the target odor is urine odor
  • the at least one olfactory receptor polypeptide is: A polypeptide comprising the amino acid sequence represented by SEQ ID NO: 6; and 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more, and even more preferably, with the amino acid sequence represented by SEQ ID NO: 6 Is a polypeptide which is 98% or more, preferably 99% or more, and has a response to a urine odor causing substance,
  • test substance is preferably a substance different from the target odor causing substance.
  • ⁇ 14> The method according to any one of ⁇ 1> to ⁇ 13>, preferably, among at least one olfactory receptor polypeptide exhibiting responsiveness to the target odor-causing substance.
  • the odorant receptor polypeptide that responds to the causative agent of the target odor is further selected.
  • Reference Example 1 Preparation of cells expressing human olfactory receptor 1
  • Cloning of human olfactory receptor gene 370 human olfactory receptors listed in Tables 1-1 and 1-2 based on sequence information registered in GenBank And genes encoding human olfactory receptors OR5AN1, OR10G4, and OR9Q2 (SEQ ID NOs: 1, 3, and 5 respectively) were cloned. Each gene was cloned by PCR using human genomic DNA female (G1521: Promega) as a template.
  • Each gene amplified by the PCR method is incorporated into a pENTR vector (Invitrogen) according to the manual, and NotI and AscI prepared downstream of the Flag-Rho tag sequence on the pME18S vector using the NotI and AscI sites present on the pENTR vector. Recomposed to the site.
  • Example 3 Production of olfactory receptor-expressing cells
  • HEK293 cells each expressing 370 types of human olfactory receptors were produced.
  • a reaction solution having the composition shown in Table 2 was prepared and allowed to stand in a clean bench for 15 minutes, and then 4.4 ⁇ L was added to each well of a 384 well plate (BioCoat).
  • 40 ⁇ L of HEK293 cells (20 ⁇ 10 4 cells / cm 2 ) were seeded in each well and cultured for 24 hours in an incubator maintained at 37 ° C. and 5% CO 2 .
  • Example 1 2 HEK293 cells expressing human olfactory receptors OR5AN1, OR10G4, OR9Q2 or OR1A1 were prepared.
  • a reaction solution having the composition shown in Table 3 was prepared and allowed to stand in a clean bench for 15 minutes, and then 10 ⁇ L was added to each well of a 96-well plate (BioCoat).
  • HEK293 cells (3 ⁇ 10 5 cells / cm 2 ) were seeded in 90 ⁇ L each well, and cultured for 24 hours in an incubator maintained at 37 ° C. and 5% CO 2 .
  • cells (Mock) under conditions that do not express olfactory receptors were also prepared and used in the experiment in the same manner.
  • Luciferase Assay The olfactory receptor expressed in HEK293 cells is conjugated with intracellular G ⁇ s to activate adenylate cyclase, thereby increasing the amount of intracellular cAMP.
  • a luciferase reporter gene assay was used to monitor the increase in intracellular cAMP level as a luminescence value derived from the firefly luciferase gene (fluc2P-CRE-hygro).
  • a renilla luciferase gene fused downstream of the CMV promoter hRluc-CMV was simultaneously introduced, and used as an internal standard for correcting errors in gene transfer efficiency or cell number.
  • the luciferase activity was measured using a Dual-Glo TM luciferase assay system (Promega) according to the operation manual of the product.
  • a value fLuc / hRluc obtained by dividing the luminescence value derived from firefly luciferase by the luminescence value derived from Renilla luciferase was calculated.
  • a value obtained by dividing fLuc / hRluc induced by odor substance stimulation by fLuc / hRluc in a cell not subjected to odor substance stimulation was calculated as a fold increase and used as an index of response intensity. Dose response curves were analyzed using GraphPad Prism.
  • Example 1 Response of olfactory receptor to odorant 1) Identification of olfactory receptor responding to odorant The medium was removed from the culture of olfactory receptor-expressing cells prepared according to Reference Example 1, and the odorant (Muscone, Guiacol or p-) Cresol) was added. 30 ⁇ L of Muscone or Guaiacol-containing DMEM medium (Nacalai) was added to each well of the 384-well plate containing the culture (final concentrations: Muscone 100 ⁇ M, Guaicol 1 mM). In addition, 75 ⁇ L of CD293 medium (Invitrogen) containing p-Cresol was added to each well of a 96-well plate containing the culture (final concentration 1 mM).
  • the luciferase assay is performed by the method of Reference Example 2 to determine the response intensity of the olfactory receptor to the odorant ( fold increase) was measured.
  • the results are shown in FIG.
  • the vertical axis represents the relative response intensity of each receptor-expressing cell to the odor stimulation when the response intensity under the condition without odor stimulation is 1.
  • OR5AN1, OR10G4, and OR9Q2 were identified as receptors that gave the highest responsiveness to Muscone, Guiacol, and p-Cresol, respectively.
  • OR9Q2 Odor substance concentration dependence of olfactory receptor response According to the methods described in Reference Examples 1 and 2, the response of OR9Q2 to different concentrations of p-Cresol was measured. As a result, OR9Q2 showed a p-cresol concentration-dependent response and was confirmed to be a p-Cresol receptor (FIG. 2).
  • Example 2 Action of odorant substance on olfactory receptor 1 Measurement of olfactory receptor response The medium was removed from the culture of olfactory receptor-expressing cells prepared according to Reference Example 1, and from 0.3 ⁇ M in DMEM medium (Nacalai Tesque). 75 ⁇ L of a solution containing an odorant prepared to 100 ⁇ M was added. After culturing the cells in a CO 2 incubator for 3 to 4 hours to fully express the luciferase gene in the cells, the luciferase assay is performed by the method of Reference Example 2, and the response intensity of the olfactory receptor to the odorant (fold increase) ) was measured.
  • OR5AN1 is an olfactory receptor that responds to musk fragrances.
  • OR5AN1 responded to these substances in a concentration-dependent manner (FIG. 3). These responses were dependent on OR5AN1, since they were not observed in cells that do not express OR5AN1 (Mock).
  • Ambrettolide, Phenyl ethyl alcohol (PEA), Lyral®, and Cis-3-hexanol did not cause an OR5AN1 response.
  • OR1A1 (FIG. 1) showing weaker responsiveness to Muscone than OR5AN1 was also activated by PEA and Cis-3-hexanol (FIG. 4). It was confirmed that OR10G4 has responsiveness to Guiacol and Ethylvanillin (FIG. 5A).
  • OR9Q2 as shown in FIG. 2, responsiveness to p-Cresol, which is a urine odor-causing substance, was confirmed, and responsiveness to p-Creyl Acetate, p-Creyl iso butyrate, and p-Methyl quinoline was further improved. Was found (FIG. 5B). On the other hand, it was found that neither OR10G4 nor OR9Q2 has responsiveness to Muscone (FIG. 5C).
  • Example 3 Sensory Evaluation of Cross Adaptation Action by Odor Substance 1
  • a target odor substance was added to a glass bottle (Saiyo Glass No. 11, volume 110 mL) to obtain a target sample.
  • Muscone As the target odor substance, Muscone, Guiacol or p-Cresol was used.
  • the Muscone used was a cotton ball soaked with 1 mg.
  • 1 mL of 10 ppm mineral oil (Sigma-Aldrich) solution was used.
  • a test substance was added to a glass bottle to obtain a test sample.
  • Ethylvanillin powder As a test substance, 5 mg of Ethylvanillin powder, or 1 mL of p-Cresyl Acetate, p-Creyl isobutyrate, or p-Methyl quinoline mineral oil (Sigma-Aldrich) solution prepared to 1000 ppm was used.
  • the sensory test was conducted in a single blind manner by 5 to 8 panelists. The panelist was first presented with the target sample and the odor intensity was answered. The test samples were then presented for 2 minutes or until no odor was detectable. Then, the target sample was again presented and the odor intensity was evaluated. This was set as 1 set, and 4 sets per person per day were set as the upper limit. There was a break of at least 10 minutes between each set.
  • the intensity of the target odor evaluated was entered on a straight line of 9.5 cm showing the scales of “No Odor” and “Strong Odor” at both ends, respectively.
  • the distance (A) between the target odor intensity entry position and No Odor in the first evaluation and the distance (B) between the target odor intensity entry position and No Odor in the second evaluation are obtained, and the% odor with respect to the first evaluation Intensity (% Oor intensity of initial estimate) [B / A * 100-100] was calculated.
  • the lower this value is, the stronger the intensity of the target odor smelled at the second time is compared with the first time, that is, the stronger the cross adaptation. If this value is ⁇ 100%, it means that the target odor was not felt at all for the second time.
  • OR10G4 is the olfactory receptor having the highest response to the odor of Guiacol (FIG. 1).
  • the odor of Guiacol was cross-adapted by Ethylvanillin that activates OR10G4 (FIG. 6B).
  • the odor of Guiacol was not cross-adapted by Muscone that did not activate OR10G4, and the smell of Ethylvanillin was not cross-adapted by Muscone. From this result, it was shown that the principle that another substance recognized by the olfactory receptor highly reactive to the target odor causative substance causes cross-adaptation of the target odor can also be applied to OR10G4.
  • Muscone that does not activate OR9Q2 does not cause cross adaptation to the odor of p-Cresol, nor to the odor of p-Cresyl Acetate, p-Cresyl iso butyrate, and p-Methyl quinoline. It was.
  • the present invention provides a novel method for identifying an odorant capable of suppressing a target odor based on cross-adaptation, using activation of an olfactory receptor response as an index.

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Abstract

L'invention concerne un procédé de recherche d'une substance qui élimine une odeur cible par adaptation croisée. Le procédé de sélection d'une substance qui induit une adaptation croisée vis-à-vis d'une odeur cible comprend : la recherche de polypeptides de récepteurs olfactifs et l'identification de l'un d'entre eux qui répond à la substance responsable de l'odeur cible ; l'addition d'une substance de test différente de la substance responsable de l'odeur cible et la mesure de la réponse ; et la sélection de la substance de test qui a activé la réponse du polypeptide d'un récepteur olfactif comme étant la substance qui induit une adaptation croisée vis-à-vis de l'odeur cible.
PCT/JP2016/065656 2015-05-29 2016-05-27 Procédé de sélection d'une substance permettant d'éliminer une odeur Ceased WO2016194788A1 (fr)

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WO2021125139A1 (fr) 2019-12-19 2021-06-24 花王株式会社 Procédé d'amélioration de la sensibilité olfactive
EP3670656A4 (fr) * 2017-08-17 2021-10-13 Komi Hakko Corporation Procédé de quantification des odeurs, cellules utilisées dans ce procédé et procédé de production desdites cellules
WO2022122122A1 (fr) * 2020-12-08 2022-06-16 Symrise Ag Médicament pour lutter contre des états inflammatoires de la peau humaine (i)
WO2022270481A1 (fr) 2021-06-22 2022-12-29 花王株式会社 Procédé d'expression de récepteur olfactif et procédé de mesure de réponse
JP2023043978A (ja) * 2021-09-17 2023-03-30 花王株式会社 アセトイン臭抑制剤の評価及び／又は選択方法
CN115902128A (zh) * 2023-02-08 2023-04-04 汉王科技股份有限公司 嗅觉受体在识别4-乙基愈创木酚中的用途和检测4-乙基愈创木酚的方法
WO2023243495A1 (fr) 2022-06-16 2023-12-21 花王株式会社 Procédé d'analyse d'un récepteur conjugué à une protéine g

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JP2005053887A (ja) * 2003-08-07 2005-03-03 Kao Corp 体臭に対する嗅覚の感度を低下させる方法
WO2012029922A1 (fr) * 2010-09-03 2012-03-08 花王株式会社 Procédé de recherche d'un agent d'élimination des mauvaises odeurs, agents d'élimination des mauvaises odeurs et procédé d'élimination des mauvaises odeurs
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EP3670656A4 (fr) * 2017-08-17 2021-10-13 Komi Hakko Corporation Procédé de quantification des odeurs, cellules utilisées dans ce procédé et procédé de production desdites cellules
WO2021125139A1 (fr) 2019-12-19 2021-06-24 花王株式会社 Procédé d'amélioration de la sensibilité olfactive
WO2022122122A1 (fr) * 2020-12-08 2022-06-16 Symrise Ag Médicament pour lutter contre des états inflammatoires de la peau humaine (i)
WO2022270481A1 (fr) 2021-06-22 2022-12-29 花王株式会社 Procédé d'expression de récepteur olfactif et procédé de mesure de réponse
JP2023043978A (ja) * 2021-09-17 2023-03-30 花王株式会社 アセトイン臭抑制剤の評価及び／又は選択方法
JP7757102B2 (ja) 2021-09-17 2025-10-21 花王株式会社 アセトイン臭抑制剤の評価及び／又は選択方法
WO2023243495A1 (fr) 2022-06-16 2023-12-21 花王株式会社 Procédé d'analyse d'un récepteur conjugué à une protéine g
CN115902128A (zh) * 2023-02-08 2023-04-04 汉王科技股份有限公司 嗅觉受体在识别4-乙基愈创木酚中的用途和检测4-乙基愈创木酚的方法

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