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WO 2018/110672 Al 21 June 2018 (21.06.2018) W !P O PCT

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WO 2018/110672 Al 21 June 2018 (21.06.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/110672 Al 21 June 2018 (21.06.2018) W !P O PCT (51) International Patent Classification: G01N 33/50 (2006.01) G01N 33/566 (2006.01) (21) International Application Number: PCT/JP20 17/044979 (22) International Filing Date: 14 December 2017 (14.12.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 16306680.6 14 December 2016 (14.12.2016) EP (71) Applicant: TAKASAGO INTERNATIONAL CORPO¬ RATION [JP/JP]; 37-1, Kamata 5-chome, Ota-ku, Tokyo, 1448721 (JP). (72) Inventors: WARR Jonathan; 167 boulevard Malesherbes, Paris, 75017 (FR). WINNIG Marcel; c/o Axxam SpA, OpenZone-via Meucci 3, Bresso-Milan, 20091 (IT). (74) Agent: EIKOH PATENT FIRM, P.C.; Toranomon East Bldg. 10F, 7-13, Nishi-Shimbashi 1-chome, Minato-ku, Tokyo, 1050003 (JP). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) l o - 54 tle METHOD FOR IDENTIFYING MALODOUR COUNTERACTANTS 00 (57) Abstract: The invention relates to a method for determining whether a test compound can counteract malodour from a sulphur © odorant. The method includes contacting the test compound and the sulphur odorant with an olfactory receptor OR4E2, and comparing the binding of the OR4E2 to the sulphur odorant, or the activity of the OR4E2, in the presence and in the absence of the test compound. Description Title of Invention: METHOD FOR IDENTIFYING MALODOUR COUNTERACTANTS Technical Field [0001] The invention relates to a method for identifying compounds that can counteract malodours, notably malodours from sulphur odorants. Background Art [0002] Humans perceive an immense variety of chemicals as having distinct odours. Odour perception initiates in the nose, where odorants are detected by a large family of olfactory receptors (ORs). [0003] The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCRs) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. [0004] Volatile compounds of natural or artificial origin can be detected by a specific set of G-protein coupled receptors located in the respiratory epithelium. It has been proposed that one odorant is capable of activating multiple olfactory receptors (ORs) and that one OR is capable of detecting different odorants (NPL 1). The human genome contains -400 intact olfactory receptor genes belonging to two main classes. Class I, "fish-like receptors" ORs presumably detect water soluble odorants, whereas class II "tetrapod specific receptors" ORs are supposed to respond to airborne volatiles (NPL 2). [0005] A mouse olfactory receptor was recently identified, which responds to (methylthio)methanethiol in heterologous cells (NPL 3). [0006] Human body odour is generated from natural materials present on the skin surface and secretions from the sweat and sebaceous glands. These materials are converted to characteristic odourous compound through oxidative degradation or metabolism by skin microbes. [0007] Human apocrine sweat gland secretions are known to produce a highly individual scent upon the action of skin flora that are present in high concentrations in the armpit. Volatile steroids, aliphatic, branched and linear fatty acids have been reported as major contributors to human axillary malodour. 3-hydroxy-3-methyl-2-hexanoic acid was in particular found to originate from a glutamine conjugate present in axillary secretions (NPL 4). [0008] Sulphur-containing compounds have also been found to be contributors of human axillary malodour (NPL 4; NPL 5). Sulphur-containing compounds have also been identified on worn laundry from the catabolism of L-methionine (NPL 6), and from urine (NPL 7). [0009] Sulphur containing materials are also sometimes deliberately added to consumer or industrial products as active ingredients, for example thioglycolic acid or salts and cysteine for hair treatment products, and give the product an undesirable base odour that needs to be overcome. Citation List Non Patent Literature [0010] NPL 1: Malnic B, Hirono J, Sato T, Buck LB. "Combinatorial receptor codes for odors." Cell 1999 96(5):713-23 NPL 2: Glusman G, Bahar A, Sharon D, Pilpel Y, White J, Lancet D. "The olfactory receptor gene superfamily: data mining, classification, and nomenclature. Mamm." Genome 2000 11(1 1): 1016-23 NPL 3: Duan X, Block E, Li Z, Connelly T, Zhang J, Huang Z, Su X, Pan Y, Wu L, Chi Q, Thomas S, Zhang S, Ma M, Matsunami H, Chen GQ, Zhuang H. "Crucial role of copper in detection of metal-coordinating odorants." Proc. Natl. Acad. Sci. USA 2012 109(9):3492-7 NPL 4: Troccaz. "The biosynthetic pathway of sulphur-containing molecules in Human Axillary Malodor: from precursors to odorous volatiles." These de doctorat : Univ. Geneve, 2009, no. Sc. 4102 (https://archive-ouverte.unige.en/unige:4563) NPL 5: Natsch A, Schmid J, Flachsmann F. "Identification of odiferous sulfany- lalkanols in human axilla secretions and their formation through cleavage of cysteine precursors by a C-S lyase isolated from axilla bacteria." Chemistry & Biodiversity 2004 1(7): 1058- 1072 NPL 6: Denawaka C, Fowlis, I, Dean J. "Source, impact and removal of malodour from soiled clothing." Journal of Chromatography A 2016 (1438): 216-225 NPL 7: Troccaz M, Niclass Y, Anziani P, Starkenmann C. "The influence of thermal reaction and microbial transformation on the odour of human urine." Flavour & Fragrance Journal 2013 (28) : 200-211. NPL 8: Li S, Ahmed L, Zhang R, Pan Y, Matsunami H, Burger JL, Block E, Batista VS, Zhuang H. "Smelling sulfur: copper and silver regulate the response of human odorant receptor OR2T1 1 to low-molecular- weight thiols." Journal of the American Chemical Society 2016 (doi:10.1021/jacs6b06983) NPL 9: Noe F, Polster J, Geithe C, Kotthoff M, Schieberle P, Krautwurst D. OR2M3: "A highly specific and narrowly tuned human odorant receptor for the sensitive detection of onion key food odorant 3-mercapto-2-methylpentan-l-ol." Chemical Sciences 2016, 00:1-16 (doi:10.1093/chemse/bjwll8) NPL 10: Saito H, Kubota M, Roberts RW, Chi Q, Matsunami H. "RTP family members induce functional expression of mammalian odorant receptors." Cell 2004 119(5):679-91 NPL 11: Von Dannecker LE, Mercadante AF, Malnic B. "Ric-8B, an olfactory putative GTP exchange factor, amplifies signal transduction through the olfactory- specific G-protein Galphaolf." J Neurosci. 2005 Apr 13;25(15):3793-800 NPL 12: Von Dannecker LE, Mercadante AF, Malnic B. "Ric-8B promotes functional expression of odorant receptors." Proc. Natl. Acad. Sci. USA 2006 103(24):9310-4 NPL 13: Bufe B, Hofmann T, Krautwurst D, Raguse JD, Meyerhof W. "The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides." Nat. Genet. 2002 32(3):397-401 Summary of Invention Technical Problem [001 1] It has now been found that a human olfactory receptor, OR4E2, responds to sulphur odorants. Accordingly the use of this polypeptide is contemplated for identifying compounds which can counteract the perception of malodour from sulphur odorants. Solution to Problem [0012] In one aspect, the invention relates to a method for determining whether a test compound can counteract the perceived (smelt) malodour from a sulphur odorant, the method comprising the steps of: a) contacting the OR4E2 polypeptide with a sulphur odorant, in the presence and in the absence of the test compound under conditions permitting the binding of said sulphur odorant to OR4E2 or permitting the activation of OR4E2 by said sulphur odorant; and b) comparing the binding of OR4E2 to said sulphur odorant, or the activity of OR4E2, in the presence and in the absence of the test compound, wherein an inhibition of the binding or a decrease in activity in the presence of the test compound, relative to the binding or activity in the absence of the test compound, identifies the test compound as a compound that can counteract the perceived malodour from the sulphur odorant. [0013] In another aspect, the invention relates to an anti-malodour composition comprising a compound identified by the above-mentioned method. [0014] In another aspect, the invention relates to household, laundry, personal care, animal care or industrial products comprising a compound identified by the above-mentioned method, or an anti-malodour composition as defined above.
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