This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing—which enables rapid reaction with an endogenous signaling electrophile—is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing.

中文翻译：

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特权亲电传感器：共价药物开发的资源

该观点描述了氧化还原信号传导如何影响特定酶同工型的活性，以及​​如何利用此特性进行合理的药物设计。近年来，共价药物流行起来，并且有几篇报道夸大了开发不可逆抑制剂的普遍优点。实际上，许多现代药物都包含亲电子附件。一些人调用了劫持活跃地点亲核试剂的弹头，而另一些人则利用了不参与酶促化学反应但准备与亲电子试剂结合/反应的旁观者亲核侧链。最新数据表明，固有的亲电试剂感应（可与内源性信号亲电试剂快速反应）是开发共价药物的典型资源。例如，基于最近的工作记录了同工型特异性亲电试剂的发现，同工酶非特异性药物可以通过劫持特权第一响应者亲电半胱氨酸来转化为同工酶特异性类似物。由于此方法的目标是功能相关的半胱氨酸，因此我们可以同时利用与氧化还原感应相关的酶先前未开发的月光作用。