Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.
Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.
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DOI：
10.1016/j.chembiol.2017.02.003
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发表时间：
2017-03-16
影响因子：
8.6
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Smith CE;Soti S;Jones TA;Nakagawa A;Xue D;Yin H
非甾体抗炎药（NSAIDs）是世界上最常用的药物之一。虽然非甾体抗炎药作为环氧化酶（COX）抑制剂的作用已被证实，但其他靶点可能有助于抗炎。在这里，我们报道了半胱天冬酶作为非甾体抗炎药家族药物如布洛芬、萘普生和酮乐酸在体外和体内生理浓度下的新药理学靶点。我们在体外和细胞培养中对caspase活性进行了表征，并结合计算模型和生物物理分析来确定其作用机制。我们观察到抑制半胱天冬酶的催化作用可以减少细胞死亡和促炎细胞因子的产生。此外，非甾体抗炎药对半胱天冬酶的抑制是不依赖于cox的，这代表了一种新的抗炎机制。这一发现扩展了现有的非甾体抗炎药的抗炎行为，对患者安全和下一代药物设计具有重要意义。Smith等人报道了半胱天冬酶作为一般非甾体抗炎药药理靶点的鉴定和表征。体外和体内均发生生理相关浓度的抑制，并扩展了NSAID的抗炎机制。
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID-family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX-independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design. Smith et al. report the identification and characterization of caspases as general NSAID pharmacological targets. Inhibition occurs at physiologically relevant concentrations both in vitro and in vivo, and expands the NSAID anti-inflammatory mechanism.