EXPRESSION OF HUMAN RENIN FROM CLONED GENES

高血压是一个严重和普遍的医学问题。 尽管多种 目前存在控制高血压的方法，许多患者 可以受益于新的抗高血压药物， 目前可用的。 肾素抑制剂构成了一个潜在的类别 高活性但特异性的抗高血压药物。 设计有用的肾素抑制剂的一个障碍是缺乏 关于酶结构的详细信息。 纯的人 肾素很难获得，而且迄今为止， 进行了晶体学分析。 建议使用cDNA 和编码人肾素的基因组克隆，以在 足以建立其晶体结构的量。 提出了用于合成前肾素和成熟的 哺乳动物细胞中的肾素和细菌中的成熟肾素。 拟 在第一阶段，将进行适当的建设， 为获得所需的表达产物而建立。 二期 将包括酶的大规模生产和纯化。 大量纯人肾素的可用性将允许结构化的 进行研究，并允许直接评估 新合成的肾素抑制剂的活性。

Hypertension is a serious and widespread medical problem. While a variety of approaches currently exist for controlling hypertension, many patients could benefit from new antihypertensive drugs that are more specific than those presently available. Renin inhibitors constitute a potential class of highly active yet specific antihypertensive agents. One impediment to the design of useful renin inhibitors is the lack of detailed information concerning the structure of the enzyme. Pure human renin is very difficult to obtain and as yet, no 3-dimensional crystallographic analysis has been performed. It is proposed to use cDNA and genomic clones coding for human renin to produce the enzyme in quantities sufficient for establishing its crystal structure. Constructions are proposed for the synthesis of both prorenin and mature renin in mammalian cells and for mature renin in bacteria. It is proposed that in Phase I, appropriate constructions will be made and that conditions will be established for obtaining the desired expressed products. Phase II will encompass the larger scale production and purification of the enzyme. The availability of large amounts of pure human renin will allow structural studies to be performed as well as allow for the direct assessment of the activity of newly synthesized renin inhibitors.