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(12) Patent Application Publication (10) Pub. No.: US 2009/0178153 A1 Gaitanaris Et Al US 20090178153A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0178153 A1 Gaitanaris et al. (43) Pub. Date: Jul. 9, 2009 (54) GPROTEIN COUPLED RECEPTORS AND Related U.S. Application Data USES THEREOF (63) Continuation of application No. 10/527,265, filed on Jan. 26, 2006, now abandoned, filed as application No. (75) Inventors: George A. Gaitanaris, Seattle, WA PCT/US03/28226 on Sep. 9, 2003. (US); John E. Bergmann, Mercer (60) Provisional application No. 60/409,303, filed on Sep. Island, WA (US); Alexander 9, 2002, provisional application No. 60/461.329, filed Gragerov, Seattle, WA (US); John on Apr. 9, 2003. Hohmann, La Conner, WA (US); Publication Classification Fusheng Li, Seattle, WA (US); (51) Int. Cl. Linda Madisen, Seattle, WA (US); AOIK 67/027 (2006.01) Kellie L. McIlwain, Washington, CI2O I/68 (2006.01) DC (US); Maria N. Pavlova, A63L/7088 (2006.01) Seattle, WA (US); Demitri GOIN 33/53 (2006.01) Vassilatis, Seattle, WA (US); CI2N IS/00 (2006.01) Hongkui Zeng, Shoreline, WA CI2N 5/10 (2006.01) (US) A61R 49/00 (2006.01) (52) U.S. Cl. .............. 800/18: 530/300: 536/23.1; 435/6; Correspondence Address: 514/44; 435/7.2: 800/21: 435/325; 424/9.2 SEED INTELLECTUAL PROPERTY LAW (57) ABSTRACT GROUP PLLC The present invention provides GPCR polypeptides and poly 701 FIFTHAVE, SUITE 5400 nucleotides, recombinant materials, and transgenic mice, as SEATTLE, WA 98104 (US) well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diag nosis and treatment of diseases and disorders. The invention (73) Assignee: OMEROS CORPORATION, also provides methods for identifying compounds (e.g., ago Seattle, WA (US) nists or antagonists) using the GPCR polypeptides and poly nucleotides of the invention, and for treating conditions asso ciated with GPCR dysfunction with the GPCR polypeptides, (21) Appl. No.: 12/243,731 polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders (22) Filed: Oct. 1, 2008 associated with inappropriate GPCR activity or levels. 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Patent Application Publication Jul. 9, 2009 Sheet 16 of 31 US 2009/0178153 A1 FIG. 1P Patent Application Publication Jul. 9, 2009 Sheet 17 of 31 US 2009/0178153 A1 Peptide 4-3ap?dadonnaNt|| zu?oneuploadc| X93)C HYJNS)C u?ssaudose.A[ Patent Application Publication Jul. 9, 2009 Sheet 18 of 31 US 2009/0178153 A1 Peptide |?wap?dedojn?NC() r (quoo)vsselo Patent Application Publication Jul. 9, 2009 Sheet 19 of 31 US 2009/0178153 A1 Patent Application Publication Jul. 9, 2009 Sheet 20 of 31 US 2009/0178153 A1 LIVUB?diòt Patent Application Publication Jul. 9, 2009 Sheet 22 of 31 US 2009/0178153 A1 Patent Application Publication Jul. 9, 2009 Sheet 23 of 31 US 2009/0178153 A1 ???UTEH 18ue?dioC BIAE! Patent Application Publication Jul. 9, 2009 Sheet 24 of 31 US 2009/0178153 A1 Patent Application Publication Jul. 9, 2009 Sheet 25 of 31 US 2009/0178153 A1 FIG. 2I Patent Application Publication Jul. 9, 2009 Sheet 26 of 31 US 2009/0178153 A1 Genes g Hypothalamus Amygdala Brain Stem Cerebellum Cortex Frontal Cortex Hippocampus Striatum Thalamus Adrenal Colon intestine Kidney Liver Lung Muscle Ovary PBL Prostate Skin Spleen Stornach Tests Thymus Thyroid Uterus Patent Application Publication Jul. 9, 2009 Sheet 27 of 31 US 2009/0178153 A1 - i s Slug? : polku Snuku SSe OleOS UeedS UdS eleSOJ T8 KeAO eoSW Bun JA Keply augSeu UOOO eUpW SLJeet uneS SndueoOdd x800 euo 380) Uneq880 JeSuel SnujeetnodES Patent Application Publication Jul. 9, 2009 Sheet 28 of 31 US 2009/0178153 A1 £OET LOET ZOET ZE){ Patent Application Publication Jul. 9, 2009 Sheet 29 of 31 US 2009/0178153 A1 Patent Application Publication Jul. 9, 2009 Sheet 30 of 31 US 2009/0178153 A1 €?JISS, (If’50IH Patent Application Publication Jul. 9, 2009 Sheet 31 of 31 US 2009/0178153 A1 US 2009/0178153 A1 Jul. 9, 2009 GPROTEIN COUPLED RECEPTORS AND polypeptide listed in Table 2; (c) polypeptides having at least USES THEREOF 90%.95%,97%.98%, or 99% sequence identity to a polypep tide listed in Table 2; and (d) polypeptides listed in Table 2. REFERENCE TO TABLE SUBMITTED ON 0008 Polypeptides of the present invention also include COMPACT DISC variants of the aforementioned polypeptides, including all 0001 Pursuant to PCT Administrative Instruction S 801 allelic forms and splice variants. Such polypeptides vary from (a), Table 35 is submitted herewith in triplicate on compact the reference polypeptide by insertions, deletions, and Sub disc as “50001.007WO3 Table 35.txt, created on Sep. 8, stitutions that may be conservative or non-conservative, or 2003 and having a size of 1,804 kB, hereby incorporated by any combination thereof. Particularly desirable variants are reference. those in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 to 2, or BACKGROUND OF THE INVENTION from 2 to 1 amino acids are inserted. Substituted, or deleted, in any combination. 0002. The invention relates to the fields of medicine and 0009 Polypeptides of the present invention also include drug discovery. polypeptides that include an amino acid sequence having at 0003 Mammalian G protein coupled receptors (GPCRs) least 30, 50, or 100 contiguous amino acids from any of the constitute a superfamily of diverse proteins with thousands of polypeptides listed in Table 2. Polypeptides of the invention members. GPCRs act as receptors for a multitude of different are desirably biologically active or are antigenic or immuno signals. Chemosensory GPCRs (csGPCR) are receptors for genic in an animal, especially in a human. sensory signals of external origin that are sensed as odors, 0010. The polypeptides of the present invention may be in pheromones, or tastes. Most other GPCRs respond to endog the form of the “mature' polypeptide, or may be a part of a enous signals, such as peptides, lipids, neurotransmitters, or larger polypeptide Such as a precursor or a fusion protein. It is nucleotides. GPCRs falling in the latter group are involved in often advantageous to include an additional amino acid numerous physiological processes, including the regulation sequence that contains secretory or leader sequences, pro of neuronal excitability, metabolism, reproduction, develop sequences, sequences that aid in purification, for instance ment, hormonal homeostasis, and behavior, and are differen multiple histidine residues, or an additional sequence for tially expressed in many cell types in the body. stability during recombinant production. 0004. Of all currently marketed drugs, greater than 30% are modulators of specific GPCRs. Only 10% of GPCRs 0011 Polypeptides of the present invention can be pre (excluding cSGPCRs) are targeted by these drugs, emphasiz pared in any suitable manner, for instance by isolation from ing the potential of the remaining 90% of the gene family for naturally occurring sources, from genetically engineered host the treatment of human disease. cells comprising expression systems, or by chemical synthe 0005. Despite the importance of GPCRs in physiology and sis, using for instance automated peptide synthesizers, or a disease, the size of the GPCR superfamily is still uncertain. combination of Such methods. For example, polypeptides of Analyses of genome sequences have generated markedly var the invention may be produced by expressing in a cell (e.g., a ied estimates (Venter, J. C. et al., Science 291, 1304-51 yeast, bacterial, mammalian, or insect cell) a vector contain (2001); Lander, E. S. et al., Nature 409, 860-921 (2001): ing a polynucleotide that encodes a GPCR of the invention Takeda, S. et al., FEBS Lett 520,97-101 (2002)). In addition, under condition in which the polypeptide (e.g., one listed in while most GPCRs are known to be selectively expressed in Table 2) is expressed. Means for preparing such polypeptides subsets of cells, the expression patterns of most GPCRs are are well understood in the art.
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