Redinbo Matthew R, Potter Philip M
Department of Chemistry, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-3290, USA.
Drug Discov Today. 2005 Mar 1;10(5):313-25. doi: 10.1016/S1359-6446(05)03383-0.
Our understanding of the detailed recognition and processing of clinically useful therapeutic agents has grown rapidly in recent years, and we are now able to begin to apply this knowledge to the rational treatment of disease. Mammalian carboxylesterases (CEs) are enzymes with broad substrate specificities that have key roles in the metabolism of a wide variety of clinical drugs, illicit narcotics and chemical nerve agents. Here, the functions, mechanism of action and structures of human CEs are reviewed, with the goal of understanding how these proteins are able to act in such a non-specific fashion, yet catalyze a remarkably specific chemical reaction. Current approaches to harness these enzymes as protein-based therapeutics for drug and chemical toxin clearance are described, as well as their uses for targeted chemotherapeutic prodrug activation. Also included is an outline of how selective CE inhibitors could be used as co-drugs to improve the efficacy of clinically approved agents.
近年来，我们对临床上有用的治疗药物的详细识别和处理的理解有了迅速发展，现在我们能够开始将这些知识应用于疾病的合理治疗。哺乳动物羧酸酯酶（CEs）是具有广泛底物特异性的酶，在多种临床药物、非法麻醉品和化学神经毒剂的代谢中起关键作用。本文综述了人CEs的功能、作用机制和结构，目的是了解这些蛋白质如何能够以这种非特异性方式发挥作用，却催化一种非常特异性的化学反应。描述了目前将这些酶用作基于蛋白质的治疗药物以清除药物和化学毒素的方法，以及它们在靶向化疗前药激活中的用途。还概述了选择性CE抑制剂如何用作辅助药物来提高临床批准药物的疗效。
