Conotoxins containing nonnatural backbone spacers: Cladistic-based design, chemical synthesis, and improved analgesic activity
Conotoxins containing nonnatural backbone spacers: Cladistic-based design, chemical synthesis, and improved analgesic activity
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DOI：
10.1016/j.chembiol.2007.02.009
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发表时间：
2007-04-01
影响因子：
--
通讯作者：
Bulaj, Grzegorz
中科院分区：
文献类型：
--
作者：
Green, Brad R.;Catlin, Philip;Bulaj, Grzegorz
来自有毒动物的富含二硫化物的神经毒素继续提供具有治疗潜力的化合物。使神经毒素最小化通常导致二硫键或关键氨基酸的去除。为了解决这个药物设计的挑战，我们探讨了由电子等排体聚合物和肽药效团组成的富含二硫化物的支架的概念。柔性间隔区，如氨基-3-氧代戊酸或6-氨基己酸，用于取代构象约束的三个二硫键桥芋螺毒素，SIIIA的部分。肽-聚合物杂交体，多肽，是基于相关肽中非保守位点的分支鉴定而设计的。氧化折叠后，多核苷酸似乎是更好的抑制剂，在背根神经节和坐骨神经的钠电流在小鼠。此外，与SIIIA相比，在小鼠的炎性疼痛模型中，聚肽似乎是显著更有效和更持久的镇痛剂。由此产生的多肽提供了一个有前途的战略转化为治疗剂的二硫键丰富的肽。
Disulfide-rich neurotoxins from venomous animals continue to provide compounds with therapeutic potential. Minimizing neurotoxins often results in removal of disulfide bridges or critical amino acids. To address this drug-design challenge, we explored the concept of disulfide-rich scaffolds consisting of isostere polymers and peptidic pharmacophores. Flexible spacers, such as amino-3-oxapentanoic or 6-aminohexanoic acids, were used to replace conformationally constrained parts of a three-disulfide-bridged conotoxin, SIIIA. The peptide-polymer hybrids, polytides, were designed based on cladistic identification of nonconserved loci in related peptides. After oxidative folding, the polytides appeared to be better inhibitors of sodium currents in dorsal root ganglia and sciatic nerves in mice. Moreover, the polytides appeared to be significantly more potent and longer-lasting analgesics in the inflammatory pain model in mice, when compared to SIIIA. The resulting polytides provide a promising strategy for transforming disulfide-rich peptides into therapeutics.