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(12) United States Patent (10) Patent No.: US 9,347,934 B2 Shekdar Et Al USOO9347934B2 (12) United States Patent (10) Patent No.: US 9,347,934 B2 Shekdar et al. (45) Date of Patent: May 24, 2016 (54) ASSAYS FOR IDENTIFYING COMPOUNDS 2008, OO38739 A1 2/2008 Li et al. THAT MODULATE BITTERTASTE 2008/0167286 A1* 7/2008 Gopalakrishnan et al. ........................ 514,21016 (71) Applicants: CHROMOCELL CORPORATION, 2010/01298.33 A1* 5/2010 Brune et al. ................. 435/721 North Brunswick, NJ (US); KRAFT FOODS GROUP BRANDS LLC, FOREIGN PATENT DOCUMENTS Northfield, IL (US) CN 1341632 A 3, 2002 CN 101583717 A 11, 2009 (72) Inventors: Kambiz Shekdar, New York, NY (US); CN 101828.111 A 9, 2010 Purvi Manoj Shah, Bridgewater, NJ WO WO-0038536 A2 7, 2000 WO WO-2004O29087 4/2004 (US); Joseph Gunnet, Flemington, NJ WO WO-2006053771 A2 5, 2006 (US); Jane V. Leland, Wilmette, IL WO WO-2007002026 A2 1/2007 (US); Peter H. Brown, Glenview, IL WO WO-2008057470 5, 2008 (US); Louise Slade, Morris Plains, NJ WO WO-2008119.195 A1 10, 2008 (US) WO WO-20081191.96 10, 2008 WO WO-20081191.97 10, 2008 (73) Assignees: Chromocell Corporation, North W WSi. A2 1929 Brunswick, NJ (US); Kraft Foods WO WO-2010O886.33 8, 2010 Group Brands LLC, Northfield, IL WO WO-2010O99983 A1 9, 2010 (US) WO WO-2013022947 2, 2013 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Bachmanov et al., Taste Receptor Genes, 2007, 27:389-414.* Behrens et al., Structural Requirements for Bitter Taste Receptor (21) Appl. No.: 14/352,620 Activation, AChemS 2009 Annual Meeting, Sarasota, FL, Poster P141, Apr. 22-26, 2009. (22) PCT Filed: Oct. 22, 2012 Brockhoff et al., “Structural Requirements of Bitter Taste Receptor Activation.” PNAS, 107(24): 11110-11 115 (2010). (86). PCT No.: PCT/US2O12/0614OO Kim et al., “Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.” Science, S371 (c)(1), 299(5610): 1221-1225 (2003). (2) Date: Apr. 17, 2014 Kuhn et al., “Bitter taste receptors for saccharin and acesulfame K.” Journal of Neuroscience, 24(45): 10260-10265 (2004). (87) PCT Pub. No.: WO2013/059836 (Continued) PCT Pub. Date: Apr. 25, 2013 (65) Prior Publication Data Primary Examiner — John Ulm US 2014/0248.639 A1 Sep. 4, 2014 (74) Attorney, Agent, or Firm — Ropes & Gray LLP. Karen Mangasarian; Brian M. Gummow Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/549,693, filed on Oct. 20, 2011. The present invention is based on applicants discovery, dis closed herein, of agonists for the TAS2R receptors TAS2R1. (51) Int. Cl. TAS2R4, TAS2R9, TAS2R13, TAS2R14, TAS2R16, GOIN33/50 (2006.01) TAS2R44, TAS2R46, and TAS2R60. The assignment of ago GOIN33/74 (2006.01) nists to these receptors makes assays for identifying com (52) U.S. Cl. pounds that modulate bitter taste possible. For example, the CPC ........ G0IN33/5044 (2013.01); G0IN33/5041 present invention provides methods of identifying com (2013.01); G0IN33/74 (2013.01); G0IN pounds that inhibit the bitter taste due to these agonists. The 2333/726 (2013.01) present invention also provides methods of identifying com (58) Field of Classification Search pounds that selectively inhibit the bitter taste due to these None agonists. The present invention further provides methods of See application file for complete search history. identifying compounds that mimic the bitter taste due these agonists. The present invention also provides methods of (56) References Cited identifying compounds that enhance the bitter taste due to U.S. PATENT DOCUMENTS these agonists. 5,853,792 A 12/1998 Zolotov et al. 2008.0003344 A1* 1/2008 Jensen et al. .................. 426,629 21 Claims, 7 Drawing Sheets US 9,347,934 B2 Page 2 (56) References Cited Winnig et al., “Saccharin: Artificial Sweetener, Bitter Tastant, and Sweet Taste Inhibitor.” Sweetness and Sweeteners, Chapter 16, pp. 230-240 Chapter DOI: 10.1021/bk-2008-0979.ch016 ACS Sympo OTHER PUBLICATIONS sium Series, vol. 979 http://pubs.acs.org/doi/abs/10.1021/bk-2008 0979.ch016. Slack et al., “Modulation of bitter taste perception by a small mol Behrens et al., “Bitter taste receptors and human bitter taste percep ecule hTAS2R antagonist.” Currently Biology, 20012): 1104-1109 tion. CMLS Cellular and Molecular Life Sciences, Birkhauser (2010). Verlag, Heidelberg, DE 6(13): 1501-1509 (2006). Slack et al., “Inhibition of Bitter Taste Receptors.” AChemS 2009 Annual Meeting, Sarasota, FL, Poster P195, Apr. 22-26, 2009. * cited by examiner U.S. Patent May 24, 2016 Sheet 1 of 7 US 9,347,934 B2 Figare : S. w 8. 3. is too too is& 8ter 88, U.S. Patent May 24, 2016 Sheet 2 of 7 US 9,347,934 B2 go sy YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY sys- sys- sys-sys-sys-yyyyyyyyyyyyy yyyyyyyyyyyyyy g g g g g g a id , s N y r er, N w U.S. Patent May 24, 2016 Sheet 3 of 7 US 9,347,934 B2 §§5. {{}}, {{}}, i-boz U.S. Patent US 9,347,934 B2 {}{}{} U.S. Patent May 24, 2016 Sheet 5 Of 7 US 9,347,934 B2 sy YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY sy- sy- sy-sys.syssy-six yyyyyyyyyyyyyyy id id s s s g c c c to it, co - \o ir, Sr. e. N --- U.S. Patent May 24, 2016 Sheet 6 of 7 US 9,347,934 B2 st r r ef, kxxxx six-yyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy a a c. d g a ce c\, cro s vs. ir, wi - N --- US 9,347,934 B2 1. 2 ASSAYS FOR DENTIFYING COMPOUNDS compound is desirable. The most common sodium chloride THAT MODULATE BITTERTASTE Substitute is potassium chloride, which, to a portion of the population, is perceived as possessing a bitter taste in addition CROSS REFERENCE TO RELATED to its salty taste. The bitter taste of potassium chloride limits APPLICATIONS the extent to which it may be used to replace sodium chloride in foods without causing undesired bitter taste for the portion This application is the National Phase entry under 35 USC of the population sensitive to it. S371 of PCT/US 12/61400, filed Oct. 22, 2012, which claims Another common food additive, sodium lactate, has a priority to U.S. Provisional Application 61/549,693, filed broad antimicrobial action, is effective at inhibiting spoilage, Oct. 20, 2011, which applications are incorporated herein by 10 and growth of pathogenic bacteria, and is commonly used in reference in their entirety. food products (e.g., meat and poultry products) to extend shelflife and increase food safety. Due to its sodium content, SEQUENCE LISTING however, sodium lactate, can be undesirable as a preservative. Potassium lactate, which has similar antimicrobial properties, The Sequence Listing associated with this application is 15 has been used in lieu of Sodium lactate. However, potassium provided in text format in lieu of a paper copy, and is hereby lactate is also associated with a bitter taste which limits the incorporated by reference into the specification. The name of extent to which it may be used to replace Sodium lactate in the text file containing the Sequence Listing is 002298-0027 foods without causing undesired bitter taste. 301-Sequence-Listing..txt. The text file is 110,076 bytes in In addition, the increasing incidence of obesity and diabe size, was created on Apr. 17, 2014, and is being Submitted tes has been attributed, in part, to the high Sugar intake of electronically via EFS Web. many diets. Accordingly, Substitution of Sugar with another Sweet tasting compound is desirable. Artificial and natural FIELD OF THE INVENTION Sugar Substitutes that may be used to reduce Sugar in foods are often associated with bitter taste which again limit the extent The present invention relates to assays for identifying bitter 25 to which these may be used to replace Sugar in foods without taste modulators. causing adverse bitter taste. For example, a common Sugar substitute is Acesulfame K, which also has a bitter taste in BACKGROUND OF THE INVENTION addition to its Sweet taste. Without being limited by theory, bitter, Sweet, and umami The sense of taste, e.g., in human, can detect at least five 30 tastants and compounds typically elicit a taste response via traditional tastes: Sweet, Sour, salty, bitter, and umami (Sa G-protein coupled receptors, while salty and Sour tastants and vory). Many nutritious substances including vegetables, compounds are typically hypothesized to elicit a taste foods, food ingredients and nutrients comprise bitter tastants response via ion channels. Bitter taste receptors belong to the and/or have a bitter taste. In addition, many pharmaceutical TAS2R (also referred to as T2R) family of G-protein coupled Substances important to maintain or improve health comprise 35 receptors that induce intracellular calcium concentration bitter tastants and/or have a bitter taste. While certain food changes in response to a bitter tastant. TAS2R receptors act products and consumer products have desirable bitter tastes, via gustducin, a taste-specific G-protein. There are at least including coffee, beer and dark chocolate, in many contexts, twenty-five different members of the TAS2Rfamily, suggest consumers dislike Such bitter tastes. For example, many con ing that the perception of bitter taste is complex, involving Sumers dislike the perception of certain bitter tastants and/or 40 several different tastant-receptor interactions. Some of the bitter taste and will avoid food or pharmaceutical products TAS2R members, e.g., TAS2R60, are orphan receptors, with an undesirable bitter tastant orbitter taste infavor of food which have not had a ligand identified. Compounds capable and pharmaceutical products that have reduced levels of of modulating the activation and/or signaling of bitter taste undesirable bitter tastants or that have reduced or that com receptors in the oral cavity and/or the gastrointestinal tract pletely lack bitter taste.
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