Szekeres Philip G
Department of Systems Research, New Frontiers Science Park, GlaxoSmithKline, Southern Way, Harlow, Essex, UK.
Recept Channels. 2002;8(5-6):297-308.
The superfamily of G protein-coupled receptors (GPCRs; 7TMs) is one of the largest families of genes identified in humans, and has a proven history of being an excellent source of drug targets. The near completion of the human genome sequencing project has allowed the identification of a plethora of sequences encoding "orphan" GPCRs--putative receptors whose natural ligand(s) remain to be discovered. In many cases, the level of sequence homology with known receptors is insufficient to be able to predict the natural ligand for these orphan receptors, although it is usually possible to determine the likely nature of the cognate ligand e.g. peptide, lipid, nucleotide etc. Deorphanizing these novel GPCRs and evaluating their biological function has become a major target of many of the major pharmaceutical companies as well as several academic groups. Since 1995 more than 50 ligands for orphan GPCRs have been discovered by using the orphan receptor as a biosensor and screening candidate compounds looking for a biological response (the so-called "reverse pharmacology" approach). Identification of the natural ligands for these receptors marks the beginning of the process of understanding the biology of these newly discovered signalling systems and the development of novel therapies targeted at them. This article will focus on the functional assays which have been used to discover ligands for orphan GPCRs.
G蛋白偶联受体超家族（GPCRs；7次跨膜蛋白）是人类已鉴定出的最大基因家族之一，并且其作为药物靶点的优质来源已有充分的历史证明。人类基因组测序项目即将完成，这使得大量编码“孤儿”GPCRs的序列得以鉴定出来，这些孤儿受体是指其天然配体仍有待发现的推定受体。在许多情况下，与已知受体的序列同源性水平不足以预测这些孤儿受体的天然配体，尽管通常能够确定同源配体可能的性质，例如肽、脂质、核苷酸等。确定这些新型GPCRs的配体并评估其生物学功能已成为许多大型制药公司以及多个学术团体的主要目标。自1995年以来，通过将孤儿受体用作生物传感器并筛选寻找生物学反应的候选化合物（即所谓的“反向药理学”方法），已发现了50多种孤儿GPCRs的配体。确定这些受体的天然配体标志着理解这些新发现的信号系统生物学以及开发针对它们的新型疗法这一过程的开始。本文将重点介绍用于发现孤儿GPCRs配体的功能测定方法。
