Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
复制标题
DOI：
10.1016/j.bcp.2020.114082
复制
发表时间：
2020-11
影响因子：
5.8
通讯作者：
Schroeder CI
中科院分区：
文献类型：
--
作者：
McMahon KL;Tay B;Deuis JR;Tanaka BS;Peigneur S;Jin AH;Tytgat J;Waxman SG;Dib-Hajj SD;Vetter I;Schroeder CI
电压门控钠（NaV）通道在疼痛感知中的作用是无可争议的。作为开发疼痛治疗剂的靶点，特别令人感兴趣的是河豚毒素抗性亚型NaV1.8和NaV1.9，这是基于将这些离子通道亚型与疼痛发病机制联系起来的动物和人类遗传学研究。然而，只有有限数量的抑制剂选择性靶向这些通道已被报道。HSTX-I是从水蛭Haemadipsa sylvestris的唾液中鉴定的肽毒素。据报道，通过两个二硫键稳定的天然23-残基肽以低微摩尔活性抑制大鼠NaV1.8和小鼠NaV1.9，因此可能代表开发对人河豚毒素抗性NaV亚型具有活性的新型调节剂的支架。我们采用一锅氧化和一步纯化法高产率合成了这种疏水肽，并采用NMR溶液光谱法测定了HSTX-I的三维溶液结构。然而，在我们的手中，合成的HSTX-I在人NaV1.8和NaV1.9下仅显示出非常适度的活性，并且在炎性疼痛的鼠模型中缺乏镇痛功效。
The role of voltage-gated sodium (NaV) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms NaV1.8 and NaV1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat NaV1.8 and mouse NaV1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant NaV isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human NaV1.8 and NaV1.9, and lacked analgesic efficacy in a murine model of inflammatory pain.
登录
查看更多内容
影响因子：
4.8
作者：
Deuis, Jennifer R.;Dekan, Zoltan;Vetter, Irina
通讯作者：
Vetter, Irina
影响因子：
4.5
作者：
Goral, R. Oliver;Leipold, Enrico;Heinemann, Stefan H.
通讯作者：
Heinemann, Stefan H.
影响因子：
3.4
作者：
LIPKIND, GM;FOZZARD, HA
通讯作者：
FOZZARD, HA
影响因子：
7.3
作者：
Payne, Claire Elizabeth;Brown, Adam R.;Stevens, Edward B.
通讯作者：
Stevens, Edward B.
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC