药物筛选--离子通道药物筛选策略.pptVIP

3） HIV-整合酶抑制剂筛选 (HIV-Integrase) 整合酶的基本功能、性质 HIV 整合酶（Integrase,IN) ： HIV 第三酶 HIV病毒pol基因3’ 端编码 32KDal 三个结构域（晶体结构均已解析） 基本功能： 催化病毒复制基本步骤－病毒双链DNA 整合到宿主DNA 作为治疗AIDS靶标优点： 人体内尚未发现该酶类似物 B A C 病毒双链DNA 整合到宿主DNA 整合酶作用部位 1. 形成整合酶、病毒DNA复合物 2. 剪切病毒DNA 3’ 末端 3. 转移病毒DNA 4. 剪切细胞DNA 5. 连接病毒DNA 和细胞DNA 药物筛选方法 SPA: Scintillation Proximity Assay SPA Bead [3H] L-731,988 DNA FLAG-integrase Biotinylated anti-FLAG antibody Amy S. Espeseth et al. (2000) PNAS SPA Bead 主要抑制剂 Diketo acids 类 L-731,988. Ryan Reinke et al (2002) A.A.C. Daria J. Hazuda et al (2000) science * 五、离子通道药物筛选 (Screening strategies for ion channel targets) I. Introduction Ion Channel Play a central role in human physiology Help regulate cellular ion homostasis Adjust the electrical activity of nerve and muscle cells 3) Control the release of transmitters and hormones. Modulation of ion channel activity represents an effective therapeutic strategy for a wide variety of disorders. II. Ion channel function Form a narrow aqueous pore spanning the membrane that selectively allows the passage of one or a few classes of ions, e.g. Na+, K+, Ca2+, or Cl-. 2. They are gated pores, allowing controlled, rather than continuous, ion flux. Gating mechanisms: “ligand-binding” (ligand-gated), “voltage-dependent mechanism (voltage-gated) III. Ion channel-related disease Long-QT syndromes (遗传性长QT综合症） (K+ ) Defects in cardiac K+ channels (occur in only 1 in 15,000 individuals and result in cardiac arrhythmia (心律失常) and sudden death). Deafness （耳聋)、Hyperinsulinemia (高胰岛素症) (K+ ) Cystic fibrosis (囊肿纤维化) 、Myopathies (肌肉病变) (Cl+ ) Hereditary hypertension (遗传性高血压) (Na+) Periodic paralysis (周期性瘫痪) (Na+) Malignant hyperthermia (恶性高热) (Ca2+) 【相关报道】