Department of Biophysics, Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Adv Sci (Weinh). 2021 Nov;8(22):e2101717. doi: 10.1002/advs.202101717. Epub 2021 Oct 17.
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.
化疗中使用的铂类化合物，如奥沙利铂，常导致患者出现周围神经病变和神经病理性疼痛，如冷感觉异常。瞬时受体电位阳离子通道亚家族 M 成员 8（TRPM8）离子通道是参与此类病理过程的关键伤害感受器。TRPM8 的直接阻断具有显著的镇痛作用，但也会引起严重的副作用，如体温过低。为了有针对性地针对冷感觉异常靶向 TRPM8 通道，我们采用优化的热点为中心的方法从头设计了环状肽 DeC-1.2。在单通道膜片钳记录中，DeC-1.2 模式特异性地抑制了配体激活的 TRPM8，但不抑制冷激活。进一步的研究表明，DeC-1.2 可消除奥沙利铂处理小鼠的冷感觉异常，而不改变体温，这表明 DeC-1.2 有可能进一步开发成为一种新型的奥沙利铂诱导的神经病理性疼痛的镇痛药。
