G蛋白偶联受体固有活性研究进展与新药开发

G蛋白偶联受体(G-prote in-coup led receptor,GPCR)是与G蛋白有信号连接的一大类受体家族,是人体内最大的膜受体蛋白家族,是一类具有7个跨膜螺旋的跨膜蛋白受体。GPCR的结构特征和在信号传导中的重要作用决定了其可以作为很好的药物靶标。目前世界药物市场上有三分之一的小分子药物是GPCR的激活剂(agon ist)或拮抗剂(antagon ist)。以其为靶点的药物在医药产业中占据显著地位。在当今前50种最畅销的上市药物中,20%属于G蛋白受体相关药物。近来的研究发现,大多数G蛋白偶联受体具有一个很重要的特性,就是具有固有活性(Constitutive ac-tivity),即无激动剂条件受体自发的维持激活并维持下游信号传导通路的活性。固有活性涉及受体、G蛋白及下游信号通路之间的关系。该文就G蛋白偶联受体固有活性概念、研究进展、反相激动剂与固有活性研究、固有活性与新药开发4个方面,进行以下论述。

Progress in research of constitutive activity of G protein-coupled receptors and their role in new drug discovery

G-protein-coupled receptos (GPCRs) are the largest superfamily of cell surface receptors, which couple G-proteins. The structures of GPCRs contain seven transmembrane domians. The unique structure and important role in the signaling transduction of GPCRs make them act as very useful drug targets. The GPCRs have great pharmacological importance and their agonists or antagonists have great potential to become the new drugs agnist diseases. So far, one third of approved small molecular drugs sold in market are the agonists or antaginists of GPCRs. Among the 50 kinds of most popular drugs approved recently, 20% of them belonged to GPCR. Recent studies demonstrate that GPCR has a very important feature: constitutive activity, which can described as the ability of a GPCR to undergo agonist-independent isomerization by which it can spontaneouly stimulates and maintains down-stream signal transduction. Constitutive activity involves interaction of receptors, G proteins, and down-stream signal transduction pathways. The present review elaborated the concept of constitutive activity, inverse agonist and progress in research of constitutive activity of G protein-coupled receptors and their role in new drug discovery.