Department of Chemistry, University College London , 20 Gordon Street, London WC1H 0AJ, United Kingdom.
Janelia Research Campus, Howard Hughes Medical Institute , Ashburn, Virginia 20147, United States.
J Am Chem Soc. 2017 Sep 20;139(37):13063-13075. doi: 10.1021/jacs.7b06506. Epub 2017 Sep 7.
Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Na1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.
蜘蛛毒液毒素，如原毒素-II（ProTx-II），作为选择性 Na1.7 通道阻滞剂，最近受到了广泛关注，有希望被开发为治疗慢性伤害感受性疼痛的先导药物。ProTx-II 是一种含有 30 个氨基酸的肽，具有三个二硫键，据报道其采用了明确的抑制半胱氨酸结（ICK）支架结构。这类肽的潜在缺点包括较差的药效学和体内二硫键潜在的混乱。为了解决这些问题，本研究报告了 ProTx-II 的硫醚键桥连类似物的固相合成，其中三个二硫键之一被硫醚键取代，并评估了这些类似物的生物学特性。我们还研究了不同线性肽前体氧化方法产生的折叠和二硫键桥接模式。最后，我们报告了 ProTx-II 的 X 射线晶体结构，达到原子分辨率；据我们所知，这是第一个未与底物结合的 ICK 蜘蛛毒液肽的晶体结构。
Zotero 插件
