南农生物技术制药第一章绪论_培训课件.ppt

* 保泰松的代谢活化 药物合成的中间体作为先导物 药物合成的中间体作为先导物 组合化学Combinatorial chemistry 同时制备含众多分子的化合物库 以代数级数增加构建块的数目，库容量则以几何级数增加 与高通量筛选（high-throughput screening, HTS）技术结合，可极大地加快先导物发现和优化的速度 反义核苷酸Antisense oligonucleotides 能够与DNA 或信使RNA发生特异性结合，分别阻断核酸的转录或翻译功能，阻止与病理过程相关的核酸或蛋白质的生物合成。这种可与DNA或信使RNA结合的互补链称作反义寡核苷酸。 Peptide Nucleic Acids (PNA) 筛选发现先导物 随机与非随机筛选 Random/nonrandom screening 高通量筛选 High-throughput screening (HTS) 虚拟筛选 Virtual screening Virtual screening 用计算机筛选的方法称为虚拟筛选，或称in silico筛选 ，成为in silico-in vitro-in vivo模式 。 用一系列“基于知识的滤片”对虚拟库“筛选”，以“浓缩”出能够满足预定标准的化合物。 这些滤片包括类药性(drug like)，药代动力学性质，毒性，知识产权问题以及与受体的互补性或与配体的相似性等，是通过数据库搜寻和计算化学实现的。 Virtual screening 抗体导向酶催化前药Antibody-Directed Enzyme Prodrug Therapy, ADEPT Target 表面抗原 单克隆抗体 ＋ 酶 前药 原药 ADEPT的酶系 羧肽酶G2（CPG2） 羧肽酶A 碱性磷酸酶 糖苷酶 青霉素酰胺酶 ?-内酰胺酶 MMCI前药＋W14F(ab)2-CPG2 MMCI作为CPG2的底物优于氮芥；原药的细胞毒作用也更强。体外绒毛膜癌细胞系试验，前药加酶活性强于前药活性100倍。体内试验可完全或明显抑制肿瘤生长。 ADEPT－?-Lactamase 癌细胞 单抗 ?-内酰胺酶 * * * * * * * * * * * * * Before we review the purpose of the meeting, let’s take a brief look at the business backdrop . . . . . . . GW is no different * * * * More tightly integrated with Discovery to allow early clinical proof of concept. Disease understanding at the molecular level underpins the entire process More predictive: Tightly defined disease and hence patient subtypes - move to ‘learn and confirm model’ . Use of biomarkers and stratification of patient population to reduce trial size and complexity. Modelling simulation are at the core of the process and are used to assess not only safety and efficacy, but also commercial potential throughout Adaptive trial design and real outcomes data in ‘in-life trials’ Move away from distinct phases – focus on proof of concept followed by limited release ‘in-life’ trials done through healthcare networks – collaborative approach The whole product package (including diagnostics, devices etc) is developed simultaneously. Potential joint funding/risk sharing agreements following accelerated launch. Examples