Green Brad R, Catlin Philip, Zhang Min-Min, Fiedler Brian, Bayudan Wendi, Morrison Alex, Norton Raymond S, Smith Brian J, Yoshikami Doju, Olivera Baldomero M, Bulaj Grzegorz
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
Chem Biol. 2007 Apr;14(4):399-407. doi: 10.1016/j.chembiol.2007.02.009.
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.
来自有毒动物的富含二硫键的神经毒素不断提供具有治疗潜力的化合物。最小化神经毒素通常会导致二硫键或关键氨基酸的去除。为应对这一药物设计挑战，我们探索了由等排体聚合物和肽类药效基团组成的富含二硫键支架的概念。使用柔性间隔物，如氨基-3-氧杂戊酸或6-氨基己酸，来取代三二硫键桥连芋螺毒素SIIIA中构象受限的部分。基于对相关肽中非保守位点的系统发育鉴定，设计了肽-聚合物杂化物（多肽）。氧化折叠后，这些多肽似乎是小鼠背根神经节和坐骨神经中钠电流的更好抑制剂。此外，与SIIIA相比，在小鼠炎症性疼痛模型中，这些多肽似乎是效力显著更强且作用更持久的镇痛药。所得多肽为将富含二硫键的肽转化为治疗药物提供了一种有前景的策略。
