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(12) United States Patent (10) Patent No.: US 8,124,360 B2 Slack (45) Date of Patent: Feb

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(12) United States Patent (10) Patent No.: US 8,124,360 B2 Slack (45) Date of Patent: Feb USOO8124360B2 (12) United States Patent (10) Patent No.: US 8,124,360 B2 Slack (45) Date of Patent: Feb. 28, 2012 (54) USE OF A T1R2 NUCLEICACID SEQUENCE OTHER PUBLICATIONS TO DENTIFY TASTANTS Ishimaru Yoshiro et al: “Two families of candidate taste receptors in (75) Inventor: Jay Patrick Slack, Loveland, OH (US) fishes' Mechanisms of Development, vol. 122, No. 12, Dec. 2005, pp. 1310-1321. (73) Assignee: Givaudan S.A. (CH) Broach, J.R. and J. Thorner “High-throughput screening for drug discovery', (1996) Nature 384 (Supp.): 14-16). (*) Notice: Subject to any disclaimer, the term of this Knight and Grigliatti, "Chimeric G Proteins Extend the Range of patent is extended or adjusted under 35 Insect Cell-Based Functional Assays for Human G Protein-Coupled U.S.C. 154(b) by 32 days. Receptors” (2004) Journal of Receptors and Signal Transduction 24: 241-256. (21) Appl. No.: 12/297.695 Kenimer & Nirenberg, “Desensitization of Adenylate Cyclase to Prostaglandin E' or 2-Chloroadenosine” 1981, Mol. Pharmacol. 20: (22) PCT Filed: Apr. 19, 2007 585-591. Traynor and Nahorski, "Modulation by u-Opioid Agonists of (86). PCT No.: PCT/CH2007/000185 Guanosine-5'-O-(3-Slthio)triphosphate Binding to Membranes from Human Neuroblastoma SH-SYSY Cells' 1995, Mol. S371 (c)(1), Pharmacol. 47: 848-854. (2), (4) Date: Nov. 3, 2008 Hafner, "Cytosensor Microphysiometer: technology and recent applications', 2000, Biosens. Bioelectron. 15: 149-158. (87) PCT Pub. No.: WO2007/121599 Gijon et al., “Cytosolic Phospholipase A is Required for Macroph age Arachidonic Acid Release by Agonists That Do and Do Not PCT Pub. Date: Nov. 1, 2007 Mobilize Calcium' 2000, J.Biol. Chem., 275:20146-20156. Horton & Baxendale, “Mass Measurements of Cyclic AMP Forma (65) Prior Publication Data tion by Radioimmunoassay, Enzyme Immunoassay, and Scintillation US 2009/O176266A1 Jul. 9, 2009 Proximity Assay” 1995, Methods Mol. Biol. 41: Chap. 8, 91-105. Felley-Bosco et al., “Constitutive Expression of Inducible Nitric Related U.S. Application Data Oxide Synthase in Human Bronchial Epithelial Cells Induces c-fos and Stimulates the coMP Pathway” Am. J. Resp. Cell and mol. Biol. (60) Provisional application No. 60/793,686, filed on Apr. (1994) 11:159-164. 20, 2006. Kikkawa et al., 1982, "Calcium-activated, Phospholipid-dependent Protein Kinase from Rat Brain': Journal of Biological Chemistry; (51) Int. Cl. 257: 13341. C07K 4/705 (2006.01) Pinna & Ruzzene, “How do protein kinases recognize their sub GOIN33/567 (2006.01) strates?” 1996, Biochem. Biophys. Acta 1314: 191-225. (52) U.S. Cl. .......................... 435/7.21: 435/7.1; 435/7.2 Li et al. “Human receptors for Sweet and umami taste” 2002, Proc (58) Field of Classification Search ........................ None Natl AcadSci USA99(7), 4692-6. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — John Ulm U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Curatolo Sidoti Co., LPA; 4,115,538 A 9, 1978 Satoh et al. Joseph G. Curatolo; Salvatore A. Sidoti 5,436,128 A 7/1995 Harpold et al. 5,919,649 A 7, 1999 Habener et al. 6,955,887 B2 * 10/2005 Adler et al. .................... 435/7.2 (57) ABSTRACT 2004/0214239 A1 10, 2004 Servant 2005/OO321.58 A1 2/2005 Adler et al. Provided are functional methods using the T1R2 monomer of FOREIGN PATENT DOCUMENTS the T1R2/T1R3 Sweet receptor to identify agonists and WO WO92fO1810 2, 1992 modulators of the Sweet taste response. WO WOO1 18050 3, 2001 WO WO 2004/055048 A T 2004 WO WO2005/O15158 2, 2005 20 Claims, No Drawings US 8, 124,360 B2 1. 2 USE OF AT1R2 NUCLEIC ACID SEQUENCE monomeric partner, but the presence of both subunits (i.e. the TO DENTIFY TASTANTS T1R2/T1R3 heterodimer receptor complex for Sweet), was believed to be essential for signal transduction. CROSS REFERENCE TO RELATED Applicant found that the known T1R2 homomer forms, APPLICATIONS Surprisingly, a functional Sweet receptor that not only binds a Sweet tastant (for example perillartine, which is a synthetic This application is a national stage application of Interna oxime approximately 370-times more potent/sweet than tional Application No. PCT/CH2007/000185, filed 19 Apr. Sucrose), but is also able to elicit a functional response and 2007, which claims the benefit of U.S. Provisional Patent activate G-Proteins in the absence of T1R3. Application No. 60/793,686, filed 20 Apr. 2006 from which 10 The terms T1R2 “homomer' or “homomeric' polypeptide, applications priority is claimed, and which are incorporated protein, or receptor as used herein are meant to encompass the herein by reference. monomer, dimmer or oligomer of the T1R2 polypeptide or The invention relates to methods based on the T1R2 recep protein, as opposed to the heterodimeric T1R2.T1R3 receptor tor protein, which is used to identify sweet taste modulators complex. including Sweet tastants in functional assay methods. Assays 15 In methods according to the invention, cells expressing with T1R2 may be used to identify agents that can modulate both T1R2 and a G-protein but not T1R3, are contacted with the taste response in humans (Sweet taste modulators), and test agents, optionally in combination with known or newly thereby render certain foods more palatable or increase determined Sweet tastants, to determine the properties of said patient compliance in oral pharmaceutics and nutraceutics. agents as Sweet taste modulators. The assays may therefore be Such sweet taste modulators include sweet tastants that elicit used to identify a tested agent as Sweet tastant or modulator of a taste response in humans. the Sweet response (of the sweet tastant, T1R2, or down The detection of sweet taste is known to be mediated by a stream events). receptor comprised of two subunits, T1R2 and T1R3, which The functional effects of the agent on the receptor and are specifically expressed in taste receptor cells, and form a G-protein are determined by a suitable functional assay, with dimeric Sweet taste receptor complex (T1R2/T1R3 het 25 out limitation, for example an assay that measures changes in erodimer). Both subunits belong to the family of so-called parameters of the transduction pathways such as intracellular “G-protein coupled receptors' or GPCRs, in particular IP3 and Ca", or by other G-protein specific assays such as class-C GPCRs. labeling with GTPYS, according to techniques known in the Like most other GPCRs, the class-C receptors have a hep art. tahelical transmembrane domain (TMD). However, unlike 30 In practising the various aspects and embodiments of the other types of GPCRs, the class-C GPCRs also have a large method in relation to cloning, elucidating ligand-receptor extracellular domain composed of two parts: a “venus flytrap pairs, and finding modulators of the Sweet response, recourse module” (VFTM) that is involved in ligand binding; and a is made to conventional techniques in molecular biology, cysteine-rich domain (CRD), that contains nine highly con microbiology and recombinant technology. These include the served cysteines and that links the VFTM to the TMD. A 35 various known methods suitable for G-protein coupled recep variable length intracellular C-terminal tail completes the tors (GPCRs) including T1R2. Accordingly, the skilled per class-C receptor. son is fully apprised of such techniques and as Such they are Activation of the Sweet receptor response was thought to hereafter treated only summarily in order to more fully require both subunits of the dimeric Sweet receptor complex, describe the context of the methods. and to date, all sweeteners tested activate the T1R2/T1R3 40 heterodimer. Published tests conducted with the separate sub SUMMARY units of the human sweet receptor (T1R2 homomer or T1R3 homomer) have shown no activity, while the T1R2/T1R3 In a first aspect, provided is a method to identify an agent heterodimer responds to a broad spectrum of chemically that modulates Sweet taste signaling in taste cells, the method diverse Sweeteners, ranging from natural Sugars (Sucrose, 45 comprising: (i) contacting the cells that express a T1R2 fructose, glucose, maltose), Sweet amino acids (D-tryp homomeric Sweet receptor that responds to Sweet taste tophan), and artificial Sweeteners (acesulfame-K, aspartame, stimuli with an agent, optionally in presence of another agent; cyclamate, Saccharin, Sucralose), to Sweet tasting proteins and (ii) determining whether at least one agent affects the (monellin, thaumatin, braZZein) (compare for example Li et functional activity of said T1R2 Sweet receptor in said cells al. (2002), Proc Natl AcadSci USA99(7), 4692-6). Studies of 50 by at least one functional response in said cells; chimeric T1R receptors and site-directed mutagenesis indi wherein said T1R2 sweet receptor is selected from the group cate that the Sweet compound cyclamate binds in the TMD of consisting of a polypeptide Substantially homologous to SEQ T1R3, thereby activating the heterodimeric T1R2/T1R3 ID NO:2, a polypeptide encoded by a nucleotide substantially receptor complex. Conversely, braZZein, a Sweet protein, is homologous to SEQ ID NO:1 as determined by sequence reported to bind in the cysteine-rich domain of T1R3, thus 55 identity, and a polypeptide encoded by a nucleotide Substan activating the heterodimeric T1R2/T1R3 receptor complex. tially homologous to SEQID NO:1 as determined by hybridi T1R2 homomer binding assays are described in US sation; 20050032 158. Binding assays show binding only, as opposed wherein the Substantially homologous polypeptide has a to functional receptor activation, and are end-point-based and sequence identity of at least 69%; time consuming compared to faster functional assay that 60 wherein the Substantially homologous nucleotide as deter involve kinetic measurements. US 2005.0032158 further mined by sequence identity has a sequence identity of at least describes functional assays including cell-based assays for 64%; T1Rs, which are suitable for the known functional receptors wherein the Substantially homologous nucleotide as deter T1R1AT1R3 and T1R2AT1R3.
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