Strategies for discovering and derisking covalent, irreversible enzyme inhibitors.
Strategies for discovering and derisking covalent, irreversible enzyme inhibitors.
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DOI：
10.4155/fmc.10.21
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发表时间：
2010-06
影响因子：
4.2
通讯作者：
Cravatt BF
中科院分区：
文献类型：
--
作者：
Johnson DS;Weerapana E;Cravatt BF
本文介绍了几种共价抑制剂，包括成功药物的例子，以及新出现的治疗靶点的高选择性、不可逆转的抑制剂，如脂肪酸酰胺水解酶。共价抑制剂具有许多理想的特征，包括靶向破坏的生物化学效率提高，对药代动力学参数的敏感性降低，作用持续时间延长，超过化合物的药代动力学。必须缓解的安全性问题包括缺乏特异性和蛋白质抑制物加合物的潜在免疫原性(S)。将特别关注最近的技术，例如基于活性的蛋白质图谱，这些技术允许人们在体外和体内定义共价抑制剂的蛋白质组范围的选择性模式。例如，原则上，任何共价抑制剂都可以用可点击的标签进行修饰，以产生与原始试剂几乎无法区分的活性探针。这些探头可以应用于任何生物系统，在广泛的剂量范围内，以充分盘点他们的开和关目标。今天市场上大量通过共价机制发挥作用的药物掩盖了历史上对开发不可逆转地发挥作用的治疗性小分子的偏见。新兴的蛋白质组学技术提供了一种系统地区分安全(选择性)和有害(非选择性)共价抑制剂的方法，因此应该激励它们未来的设计和开发。
This article presents several covalent inhibitors, including examples of successful drugs, as well as highly selective, irreversible inhibitors of emerging therapeutic targets, such as fatty acid amide hydolase. Covalent inhibitors have many desirable features, including increased biochemical efficiency of target disruption, less sensitivity toward pharmacokinetic parameters and increased duration of action that outlasts the pharmacokinetics of the compound. Safety concerns that must be mitigated include lack of specificity and the potential immunogenicity of protein–inhibitor adduct(s). Particular attention will be given to recent technologies, such as activity-based protein profiling, which allow one to define the proteome-wide selectivity patterns for covalent inhibitors in vitro and in vivo. For instance, any covalent inhibitor can, in principle, be modified with a ‘clickable’ tag to generate an activity probe that is almost indistinguishable from the original agent. These probes can be applied to any living system across a broad dose range to fully inventory their on and off targets. The substantial number of drugs on the market today that act by a covalent mechanism belies historical prejudices against the development of irreversibly acting therapeutic small molecules. Emerging proteomic technologies offer a means to systematically discriminate safe (selective) versus deleterious (nonselective) covalent inhibitors and thus should inspire their future design and development.
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