Proteases as drug targets
Proteases as drug targets
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DOI：
10.1042/bss0700147
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Groom, CR
中科院分区：
文献类型：
--
作者：
Docherty, AJP;Crabbe, T;Groom, CR
用HIV蛋白酶抑制剂有效治疗艾滋病，或用血管紧张素转换酶抑制剂治疗高血压，表明蛋白酶确实是很好的药物靶点。另一方面，几家公司的基质金属蛋白酶（MMP）抑制剂在癌症和类风湿性关节炎的临床试验中都失败了。铭记MMP抑制剂的经验，本章探讨了如何从化学角度作为药物靶点的蛋白酶。它检查了最近成功的其他类药物治疗类风湿性关节炎，并强调需要考虑假定的目标在于病理生理途径，无论什么样的治疗实体将需要针对他们。随着基因组研究产生了许多可能的新药物靶点，它探索了发现蛋白水解酶的可能性，这些酶对疾病过程负有因果责任，因此可能成为更好的靶点，特别是如果它们导致开发可口服的药物。它还考虑了生物制剂对药物发现的影响，特别是生物衍生的治疗剂（如抗体）是否可能显著改变我们将蛋白酶视为靶标的方式以及用于发现治疗性抑制剂的方法。
The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.