膜蛋白质在医学中作为药靶

　　Hartmut Michel, 马普生物物理所, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main，德国

　　生物细胞构成组织 ，组织构成器官，器官构成像人这样的有机体。每一细胞被生物膜包围并被生物膜所分隔。生物膜中含有脂质与蛋白质作为其组成成分。脂质是较为被动的、被隔离的成分，而膜蛋白是较为活跃的成分。膜蛋白接受信号，通过生物膜转换信号，并放大信号。有些膜蛋白催化各种物质通过生物膜的运输，还有一些膜蛋白参与生物学的能量转换。

　　膜蛋白在医学中非常重要。用于治疗患者的大多数药物通过与膜蛋白结合而起作用，有的药物活化膜蛋白，有的药物使膜蛋白失活。从历史上看，药物的发现与药物的发展依赖于偶然所见以及传统草药。当化学家们能够在结构上合成激素、神经递质及有促效和对抗作用的酶基质的相关类似物时，药物的开发有了更为合理的方法。这一时期已被大量化学成分的自动“高通量筛选”所取代，以找出能激活或抑制与疾病相关药靶的化学成分。高通量筛选实现不了全面的预期，更多的期望寄托在基于结构的药物研制上。此方法首先需要确定药靶的精确原子结构，然后进行合理的药物设计或实际筛选，以开发新的和特效药物。膜蛋白仍然是大多数药靶的构成成分，因为完成信号转导特异性的部位是在膜蛋白。

　　基于结构的药物研制需要药靶结构的相关知识。因为膜蛋白难以处理，所以膜蛋白的结构知识很难得到。此文将讨论作者实验室的最近成果，以及获得所谓G蛋白耦合受体结构的尝试，此结构在医学上与经济学上都是最为重要的受体类型。关键问题在于需要生产足量的均匀且稳定的受体以供结构研究使用。

Membrane Proteins as Targets for Drugs in Medicine

　　Hartmut Michel, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main, Germany

　　Biological cells constitute tissues, tissues constitute organs, and organs constitute organisms like humans. Each cell is surrounded and compartmentalized by biological membranes. Biological membranes contain lipids and proteins as their constituents. The lipids are the more passive, insulating components, whereas the membrane proteins are the more active players. They receive signals, transduce them across the membrane and amplify them. Others catalyze the transport of various substances across the membranes, and others are involved in biological energy conversion. 

　　Membrane proteins are of enormous importance in medicine. Most of the drugs used to treat patients act by binding to membrane proteins, either activating or inactivating them. Historically, drug discovery and drug development have relied on accidental observations and traditional, herbal medicine. A more rational way of drug development has been introduced when chemists were able to synthesize structurally related analogues of hormones, neurotransmitters and enzyme substrates which either acted as agonists or antagonists. This phase has been replaced by automated “high-throughput screening” of huge libraries of chemical compounds which were tested for activation or inhibition of promising, disease related drug targets. High-throughput screening did not live up to the general expectations, and the big hope now resides in structure-based drug development. For this method the precise atomic structure of the drug target is required, before rational drug design or virtual screening can be employed to develop new and specific drugs. Membrane proteins will continue to constitute the majority of drug targets, because it is the membrane level where specificity in signal transduction is achieved.

　　Structure-based drug development requires knowledge of the structures of the drug target. Structural knowledge of membrane proteins is difficult to generate because membrane proteins are difficult to handle.  The recent successes of the author′s lab will be described, as well as the attempts towards getting the structures of the so-called G-protein coupled receptors, which constitute the medically and economically most important receptor class. Here the bottle neck resides in the production of sufficient amounts of homogeneous and stable receptors for structural studies.