《生物技术药物》之重组多肽蛋白质类激素药物

各论五,重组多肽、蛋白质类激素药物,激素(hormone)由腺体合成和释放，通过循环系统，作用于靶细胞周倜的微量化学信号分子。特点：内分泌信号调节系统，作用远距离靶细胞。包括两类：含氮激素和甾体激素。含氮激素：胰岛素、胰高血糖素、生长素、促性腺激素等。受体类型：,胰腺,B细胞(70%)A细胞(20%)D细胞(10%),重组胰岛素,胰岛素(insulin)胰岛素是含有51个氨基酸的小分子蛋白质，分子量为6000，胰岛素分子有靠两个二硫键结合的A链（21个氨基酸）与B链（30个氨基酸），如果二硫键被打开则失去活性。B细胞先合成一个大分子的前胰岛素原(109个氨基酸)，以后加工(-23个氨基酸)成八十六肽的胰岛素原，在细胞内的高尔基体中胰岛素原经水解(-2氨基酸)成为胰岛素(21+30)与连接肽(C肽33个氨基酸)。 胰岛素与C肽共同释入血中，也有少量的胰岛素原进入血液，但其生物活性只有胰岛素的3%-5%，而C肽无胰岛素活性。由于C肽是在胰岛素合成过程产生的，其数量与胰岛素的分泌量有平行关系，因此测定血中C肽含量可反映B细胞的分泌功能。,Beta cells in the islets of Langerhans release insulin in two phases. The first phase release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar. The description of first phase release is as follows:Glucose enters the -cells through the glucose transporter, GLUT2.Glucose goes into glycolysis and the respiratory cycle, where multiple, high-energy ATP molecules are produced by oxidation, leading to a rise in the ATP:ADP ratio within the cell.An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/Kir6.2 potassium channel (see sulfonylurea receptor). This prevents potassium ions (K+) from leaving the cell by facilitated diffusion, leading to a build up of potassium ions. As a result, the inside of the cell becomes more positive with respect to the outside, leading to the depolarisation of the cell surface membrane.On depolarisation, voltage-gated calcium ion (Ca2+) channels open which allows calcium ions to move into the cells by facilitated diffusion.An increased intracellular calcium ion concentration causes the activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol.Inositol 1,4,5-trisphosphate (IP3) binds to receptor proteins in the plasma membrane of the endoplasmic reticulum (ER). This allows the release of Ca2+ ions from the ER via IP3-gated channels, and further raises the intracellular concentration of calcium ions.Significantly increased amounts of calcium ions in the cells causes the release of previously synthesized insulin, which has been stored in secretory vesicles.,The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors。,Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which, in turn, starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5), and fatty acid synthesis (6).,Somatostatin (also known as growth hormone-inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF) or somatotropin release-inhibiting hormone.a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.,Suppresses the release of pancreatic hormones,Inhibits insulin release when somatostatin is released from delta cells of pancreasInhibits the release of glucagon,胰高血糖素,胰高血糖素（glucagon）它是由脊椎动物胰脏的胰岛细胞分泌的一种激素。29个氨基酸组成受体：G蛋白偶联受体生物学特性：促进糖、脂肪和蛋白质分解。提高血糖水平临床：低血糖,Glucagon receptor, a G protein-coupled receptor,The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.,人生长激素,Human growth hormone在脑垂体前叶合成191个氨基酸 ，单链，两个二硫键受体：生物学特性：促进蛋白质合成促进软骨细胞增殖影响糖多谢临床：生长激素缺乏症,Growth hormone (GH or HGH), also known as somatotropin or somatropin, is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. It is a type of mitogen which is specific only to certain kinds of cells. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.,GH 受体：受体酪氨酸激酶,GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1).,重组 hGH,大肠杆菌表达体系,促性腺激素类药物,Gonadotropins (or glycoprotein hormones)Gonadotropins (or glycoprotein hormones) are protein hormones secreted by gonadotrope cells of the anterior pituitary of vertebrates. This is a family of proteins, which include the mammalian hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), placental chorionic gonadotropins hCG and eCG4 and chorionic gonadotropin (CG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. The hormones LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta.Gonadotropin receptors are embedded in the surface of the target cell membranes and coupled to the G-protein system. Signals triggered by binding to the receptor are relayed within the cells by the cyclic AMP second messenger system.,卵泡刺激素,follicle-stimulating hormone (FSH)alpha 亚基92个 氨基酸和beta 亚基111 个氨基酸N端糖基化，以链间二硫键连接生物学特性：男/女男女,follicle-stimulating hormone (FSH)Follicle-stimulating hormone (FSH) is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) act synergistically in reproduction. Specifically, an increase in FSH secretion by the anterior pituitary causes ovulation.,FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached to it; two of these make the full, functional protein. The protein dimer contains 2 polypeptide units, labeled alpha and beta subunits.,FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body.,In both males and females, FSH stimulates the maturation of germ cells.In males, FSH induces Sertoli cells to secrete inhibin and stimulates the formation of sertoli-sertoli tight junctions (zonula occludens).In females, FSH initiates follicular growth, specifically affecting granulosa ce