Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
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DOI：
10.1002/cmdc.200800292
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发表时间：
2009-03
期刊：
影响因子：
3.4
通讯作者：
Bulaj, Grzegorz
中科院分区：
文献类型：
--
作者：
Han, Tiffany S.;Zhang, Min-Min;Walewska, Aleksandra;Gruszczynski, Pawel;Robertson, Charles R.;Cheatham, Thomas E., III;Yoshikami, Doju;Olivera, Baldomero M.;Bulaj, Grzegorz
二硫键稳定螺毒素的天然构象，对合成较小的类似物提出了挑战。在这项工作中，我们描述了一种最小限度类似的止痛药μ-芋螺毒素KIIIA的合成，它可以阻断两种钠通道亚型，神经元NaV1.2和骨骼肌NaV1.4。首次合成了三个KIIIA的二硫键缺陷类似物，其中去除了在C1-C9、C2-C15或C4-C16之间形成的天然二硫键。第一个桥的缺失对多肽的生物活性影响很小。为了进一步最小化这种类似物，去掉了N-末端残基，并用单个5-氨基-3-氧杂戊酸残基取代了两个非必需的Ser残基。由此产生的“多肽”类似物保留了阻断钠通道和产生镇痛的能力。到目前为止，应用于芋螺毒素的模拟多肽的方法充其量只取得了适度的进展；因此，含有主干间隔基的二硫键缺陷类似物为基于芋螺毒素的疗法的发展提供了另一种进展。
Disulfide bridges, which stabilize the native conformation of conotoxins impose a challenge in the synthesis of smaller analogs. In this work, we describe the synthesis of a minimized analog of the analgesic μ-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal NaV1.2 and skeletal muscle NaV1.4. Three disulfide-deficient analogs of KIIIA were initially synthesized in which the native disulfide bridge formed between either C1-C9, C2-C15 or C4-C16 was removed. Deletion of the first bridge only slightly affected the peptide’s bioactivity. To further minimize this analog, the N-terminal residue was removed and two non-essential Ser residues were replaced by a single 5-amino-3-oxapentanoic acid residue. The resulting “polytide” analog retained the ability to block sodium channels and to produce analgesia. Until now, the peptidomimetic approach applied to conotoxins has progressed only modestly at best; thus, the disulfide-deficient analogs containing backbone spacers provide an alternative advance toward the development of conopeptide-based therapeutics.
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