title: Deorphanization of novel peptides and their receptors.
abstract: Peptide hormones and neuropeptides play important roles in endocrine and neural signaling, often using G protein-coupled receptor (GPCR)-mediated signaling pathways. However, the rate of novel peptide discovery has slowed dramatically in recent years. Genomic sequencing efforts have yielded a large number of cDNA sequences that potentially encode novel candidate peptide precursors, as well as hundreds of orphan GPCRs with no known cognate ligands. The complexity of peptide signaling is further highlighted by the requirement for specific posttranslational processing steps, and these must be accomplished in vitro prior to testing newly discovered peptide precursor candidates in receptor assays. In this review, we present historic as well as current approaches to peptide discovery and GPCR deorphanization. We conclude that parallel and combinatorial discovery methods are likely to represent the most fruitful avenues for both peptide discovery as well as for matching the remaining GPCRs with their peptide ligands.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, 20 Penn St. HSFII Rm S251, Baltimore, Maryland 21201, USA.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ozawa
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.forename: Bryan
authors.initials: B
authors.lastname: Roth
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Kroeze
mesh_terms: D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D013058:Mass Spectrometry; D010455:Peptides / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000502:physiology*
chemical_list: D010455:Peptides; D011956:Receptors, Cell Surface
references.citation: EMBO J. 1992 Jul;11(7):2399-405
references.pmid: 1628613
references.citation: Nature. 1975 Dec 18;258(5536):577-80
references.pmid: 1207728
references.citation: Trends Pharmacol Sci. 2005 Jan;26(1):15-9
references.pmid: 15629200
references.citation: Peptides. 2006 May;27(5):1073-86
references.pmid: 16500002
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S339-46
references.pmid: 18071299
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8966-71
references.pmid: 11459929
references.citation: J Biol Chem. 2006 Feb 10;281(6):3312-20
references.pmid: 16286464
references.citation: Nature. 1999 Jul 15;400(6741):265-9
references.pmid: 10421368
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1508-13
references.pmid: 14757815
references.citation: Mol Endocrinol. 2000 Jan;14(1):160-9
references.pmid: 10628755
references.citation: Peptides. 2006 May;27(5):1087-98
references.pmid: 16494967
references.citation: Brain Res. 2006 May 4;1087(1):1-14
references.pmid: 16647048
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:43-66
references.pmid: 14744238
references.citation: Nature. 2009 Nov 12;462(7270):175-81
references.pmid: 19881490
references.citation: J Proteome Res. 2007 May;6(5):1652-65
references.pmid: 17408250
references.citation: Mol Cell Proteomics. 2007 Jun;6(6):1007-17
references.pmid: 17317658
references.citation: J Biol Chem. 1995 Sep 15;270(37):21509-16
references.pmid: 7665562
references.citation: Genome Res. 2007 Mar;17(3):320-7
references.pmid: 17284679
references.citation: Assay Drug Dev Technol. 2007 Jun;5(3):425-51
references.pmid: 17638542
references.citation: J Neurochem. 2008 Dec;107(6):1596-613
references.pmid: 19014391
references.citation: Nature. 1999 Dec 9;402(6762):656-60
references.pmid: 10604470
references.citation: Cell Mol Biol (Noisy-le-grand). 2003 Jul;49(5):713-22
references.pmid: 14528907
references.citation: Nature. 1998 May 21;393(6682):272-6
references.pmid: 9607765
references.citation: Protein Eng Des Sel. 2004 Jan;17(1):107-12
references.pmid: 14985543
references.citation: J Mol Neurosci. 2006;28(3):277-84
references.pmid: 16691015
references.citation: J Biol Chem. 1990 Feb 25;265(6):2997-3000
references.pmid: 2154467
references.citation: Cell Metab. 2006 Mar;3(3):167-75
references.pmid: 16517404
references.citation: Biosens Bioelectron. 2009 Dec 15;25(4):715-20
references.pmid: 19734032
references.citation: Cell. 2008 Oct 31;135(3):561-71
references.pmid: 18984166
references.citation: J Mass Spectrom. 2005 Feb;40(2):238-49
references.pmid: 15706629
references.citation: J Biol Chem. 1993 Mar 15;268(8):5615-23
references.pmid: 8449925
references.citation: J Biol Chem. 2005 Feb 11;280(6):4451-61
references.pmid: 15572367
references.citation: BMC Genomics. 2007 Sep 25;8:338
references.pmid: 17892602
references.citation: Mol Cell Proteomics. 2009 Jul;8(7):1638-47
references.pmid: 19339239
references.citation: Comb Chem High Throughput Screen. 2008 Mar;11(3):195-215
references.pmid: 18336213
references.citation: Curr Opin Chem Biol. 1998 Feb;2(1):31-9
references.pmid: 9667917
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):140-64
references.pmid: 17659814
references.citation: Genomics. 2006 Sep;88(3):263-73
references.pmid: 16753280
references.citation: Comb Chem High Throughput Screen. 2008 Jun;11(5):344-56
references.pmid: 18537556
references.citation: Eur J Biochem. 2000 Mar;267(6):1626-33
references.pmid: 10712592
references.citation: J Cell Biochem. 1988 Dec;38(4):279-89
references.pmid: 3149282
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12527-32
references.pmid: 18719122
references.citation: Biochem J. 1997 Nov 1;327 ( Pt 3):625-35
references.pmid: 9599222
references.citation: Anal Biochem. 2007 Jul 15;366(2):182-9
references.pmid: 17540328
references.citation: Results Probl Cell Differ. 2008;46:v-vi
references.pmid: 18634199
references.citation: Assay Drug Dev Technol. 2008 Jun;6(3):327-37
references.pmid: 18537464
references.citation: J Biol Chem. 2000 Aug 25;275(34):25965-71
references.pmid: 10851242
references.citation: J Biomol Screen. 2004 Apr;9(3):196-207
references.pmid: 15140381
references.citation: Biochem Biophys Res Commun. 2009 Sep 18;387(2):283-8
references.pmid: 19580790
references.citation: Br J Pharmacol. 2001 May;133(1):138-44
references.pmid: 11325803
references.citation: Trends Biotechnol. 1997 Dec;15(12):487-94
references.pmid: 9418303
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4903-8
references.pmid: 12679517
references.citation: Pharmacol Ther. 2006 Jun;110(3):525-32
references.pmid: 16289308
references.citation: Hum Reprod Update. 2009 Mar-Apr;15(2):203-12
references.pmid: 19109311
references.citation: Assay Drug Dev Technol. 2009 Apr;7(2):133-42
references.pmid: 19505230
references.citation: Life Sci. 2003 Dec 5;74(2-3):367-77
references.pmid: 14607265
references.citation: J Neurochem. 2006 Feb;96(4):1169-81
references.pmid: 16417576
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):1-13
references.pmid: 16803859
references.citation: FEBS Lett. 1986 May 5;200(1):1-10
references.pmid: 3516723
references.citation: Int Rev Neurobiol. 2005;65:179-209
references.pmid: 16140057
references.citation: Biochem Pharmacol. 2006 Jan 12;71(3):319-37
references.pmid: 16336942
references.citation: J Pharmacol Exp Ther. 2005 Dec;315(3):1338-45
references.pmid: 16144971
references.citation: Endocr Rev. 1980 Winter;1(1):1-27
references.pmid: 6262069
references.citation: J Biol Chem. 2003 Jul 4;278(27):24243-6
references.pmid: 12730193
references.citation: J Histochem Cytochem. 2000 Nov;48(11):1553-64
references.pmid: 11036098
references.citation: Cell. 1998 Feb 20;92(4):573-85
references.pmid: 9491897
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2383-8
references.pmid: 19179284
references.citation: Nature. 1988 Sep 22;335(6188):358-60
references.pmid: 3138543
references.citation: Biochem Biophys Res Commun. 2007 Nov 23;363(3):861-6
references.pmid: 17905198
references.citation: Arch Biochem Biophys. 1996 Jun 15;330(2):238-50
references.pmid: 8660652
references.citation: Genome Res. 2003 Jun;13(6B):1395-401
references.pmid: 12819138
references.citation: Biosens Bioelectron. 2009 Mar 15;24(7):2298-304
references.pmid: 19135356
references.citation: Biochem J. 1997 Feb 1;321 ( Pt 3):587-93
references.pmid: 9032441
references.citation: World J Gastroenterol. 2003 Jun;9(6):1174-8
references.pmid: 12800218
references.citation: J Biol Chem. 2009 May 1;284(18):12328-38
references.pmid: 19286662
references.citation: Pharmacogenomics. 2004 Sep;5(6):657-72
references.pmid: 15335287
references.citation: J Neurosci. 2000 Jan 15;20(2):639-48
references.pmid: 10632593
references.citation: Expert Rev Proteomics. 2008 Aug;5(4):603-17
references.pmid: 18761470
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W267-72
references.pmid: 16845008
references.citation: J Biol Chem. 1986 Feb 5;261(4):1815-22
references.pmid: 3944110
references.citation: J Biol Chem. 2002 Sep 13;277(37):34010-6
references.pmid: 12118011
references.citation: Biosens Bioelectron. 2010 Mar 15;25(7):1675-80
references.pmid: 20044245
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12109-14
references.pmid: 11050239
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6251-6
references.pmid: 12719537
references.citation: Cell. 2008 Feb 8;132(3):387-96
references.pmid: 18267071
references.citation: J Mass Spectrom. 2005 Feb;40(2):227-37
references.pmid: 15706630
references.citation: J Biol Chem. 1997 Oct 31;272(44):27497-500
references.pmid: 9346876
references.citation: PLoS Comput Biol. 2009 Jan;5(1):e1000258
references.pmid: 19132080
references.citation: DNA Cell Biol. 1990 Dec;9(10):789
references.pmid: 2264933