Rational Design of a Modality-Specific Inhibitor of TRPM8 Channel against Oxaliplatin-Induced Cold Allodynia.
Rational Design of a Modality-Specific Inhibitor of TRPM8 Channel against Oxaliplatin-Induced Cold Allodynia.
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针对奥沙利铂引起的冷异常性疼痛的 TRPM8 通道模态特异性抑制剂的合理设计。
DOI：
10.1002/advs.202101717
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Aierken A;Xie YK;Dong W;Apaer A;Lin JJ;Zhao Z;Yang S;Xu ZZ;Yang F
化疗中的铂类化合物（如奥沙利铂）通常会诱导患者发生周围神经病变和神经性疼痛（如冷异常性疼痛）。瞬时受体电位Melastatin 8（TRPM 8）离子通道是一种重要的伤害感受器，参与了这些病理过程。直接阻断TRPM 8表现出显著的镇痛作用，但也引起严重的副作用，如体温过低。为了选择性靶向TRPM 8通道对抗冷异常性疼痛，用优化的热点中心方法重新设计了环肽DeC-1.2。DeC-1.2模式特异性抑制TRPM 8的配体激活，但不抑制冷激活，如在单通道膜片钳记录中所测量的。进一步证明，DeC-1.2消除了奥沙利铂治疗小鼠的冷异常性疼痛，而不改变体温，表明DeC-1.2具有进一步开发作为奥沙利铂诱导的神经性疼痛的新型镇痛剂的潜力。为了选择性靶向TRPM 8通道对抗冷异常性疼痛，使用优化的热点中心方法计算设计了环肽DeC-1.2。它抑制TRPM 8的配体活化，但不抑制冷活化。DeC-1.2还消除了奥沙利铂处理小鼠的冷触诱发痛，而不改变体温，表明其作为奥沙利铂诱导的神经性疼痛的新型镇痛剂的潜力。
Platinum‐based compounds in chemotherapy such as oxaliplatin often induce peripheral neuropathy and neuropathic pain such as cold allodynia in patients. Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC‐1.2 is de novo designed with the optimized hot‐spot centric approach. DeC‐1.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single‐channel patch clamp recordings. It is further demonstrated that DeC‐1.2 abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating DeC‐1.2 has the potential for further development as a novel analgesic against oxaliplatin‐induced neuropathic pain. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC‐1.2 is computationally designed with the optimized hot‐spot centric approach. It inhibits the ligand activation of TRPM8 but not the cold activation. DeC‐1.2 also abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating its potential as a novel analgesic against oxaliplatin‐induced neuropathic pain.
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