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Orphan G‐protein‐coupled receptors: the next generation of drug targets?
Author(s) -
Wilson Shelagh,
Bergsma Derk J.,
Chambers Jon K.,
Muir Alison I.,
Fantom Kenneth G. M.,
Ellis Catherine,
Murdock Paul R.,
Herrity Nicole C.,
Stadel Jeffrey M.
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702238
Subject(s) - g protein coupled receptor , computational biology , biology , receptor , functional genomics , drug discovery , expression cloning , genetics , genomics , bioinformatics , genome , gene , peptide sequence
The pharmaceutical industry has readily embraced genomics to provide it with new targets for drug discovery. Large scale DNA sequencing has allowed the identification of a plethora of DNA sequences distantly related to known G protein‐coupled receptors (GPCRs), a superfamily of receptors that have a proven history of being excellent therapeutic targets. In most cases the extent of sequence homology is insufficient to assign these ‘orphan’ receptors to a particular receptor subfamily. Consequently, reverse molecular pharmacological and functional genomic strategies are being employed to identify the activating ligands of the cloned receptors. Briefly, the reverse molecular pharmacological methodology includes cloning and expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations, peptide libraries, and complex compound collections. The functional genomics approach involves the use of humanized yeast cells, where the yeast GPCR transduction system is engineered to permit functional expression and coupling of human GPCRs to the endogenous signalling machinery. Both systems provide an excellent platform for identifying novel receptor ligands. Once activating ligands are identified they can be used as pharmacological tools to explore receptor function and relationship to disease. British Journal of Pharmacology (1998) 125 , 1387–1392; doi: 10.1038/sj.bjp.0702238