Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences and Yunnan Province, Kunming 650223, Yunnan, China.
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17534-9. doi: 10.1073/pnas.1306285110. Epub 2013 Sep 30.
Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of µ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits NaV1.7 with an IC50 of ∼25 nM. µ-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, for which the selectivity is 32-fold. µ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. µ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemical-induced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes µ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting NaV1.7, which might be suitable for treating a wide range of human pain pathologies.
电压门控钠离子通道 NaV1.7 的人类失活突变导致先天性无痛症。因此，NaV1.7 的选择性抑制剂很可能成为治疗广泛疼痛病症的强力镇痛药。本文描述了µ-SLPTX-Ssm6a 的鉴定，这是一种来自蜈蚣毒液的独特的 46 个残基肽，对 NaV1.7 具有强效抑制作用，IC50 约为 25 nM。µ-SLPTX-Ssm6a 对所有其他人类 NaV 亚型的选择性超过 150 倍，除了 NaV1.2，其选择性为 32 倍。µ-SLPTX-Ssm6a 含有三个具有独特连接模式的二硫键，与任何以前表征的肽或蛋白没有显著的序列同源性。µ-SLPTX-Ssm6a 在化学诱导疼痛的啮齿动物模型中被证明比吗啡更有效，并且在热和酸诱导疼痛的啮齿动物模型中与吗啡等效。这项研究确立 µ-SPTX-Ssm6a 为开发针对 NaV1.7 的新型镇痛药的有前途的先导分子，它可能适合治疗广泛的人类疼痛病理。
