Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Mar Drugs. 2019 Mar 14;17(3):165. doi: 10.3390/md17030165.
Integrated venomics techniques have shown that variable processing of conotoxins from resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from , the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and therefore a drug candidate for attenuating chronic neuropathic pain. It has been found that "messy" processing of the MrIA transcripts results in the expression of MrIA analogs with different truncations of the pro-peptide that contains portions of the MrIA molecule. The aim of this study was to investigate if variable processing of the expressed peptides results in modulation of the existing hNET pharmacology or creates new pharmacologies. To this end, a number of MrIA analogs found in venom were synthesized and evaluated for their activity at hNET receptors. While several of the analogs exhibited norepinephrine transporter inhibitory activity comparable to that of MrIA, none significantly improved on the potency of conotoxin MrIA, and those analogs with disrupted pharmacophores produced greatly reduced NET inhibition, confirming previous structure-activity relationships seen on χ-class conopeptides. Additionally, analogs were screened for new activities on ion channels using calcium influx assays, although no major new pharmacology was revealed.
整合毒液组学技术表明， 来源的短肽的可变加工导致表达的短肽数量显著增加。 来自 的一种短肽， χ-芋螺毒素 MrIA， 是人类去甲肾上腺素转运体（hNET）的选择性抑制剂，因此是减轻慢性神经性疼痛的候选药物。已经发现，MrIA 转录本的“杂乱”加工导致表达具有不同前肽截断的 MrIA 类似物，该前肽包含 MrIA 分子的部分。本研究的目的是研究表达肽的可变加工是否会导致现有 hNET 药理学的调节或产生新的药理学。为此，合成了在 毒液中发现的多种 MrIA 类似物，并评估了它们在 hNET 受体上的活性。虽然一些类似物表现出与 MrIA 相当的去甲肾上腺素转运体抑制活性，但没有一种显著提高芋螺毒素 MrIA 的效力，并且那些破坏药效团的类似物产生的 NET 抑制作用大大降低，证实了之前在 χ 类芋螺肽上观察到的结构-活性关系。此外，使用钙内流测定法筛选类似物在离子通道上的新活性，尽管没有揭示出主要的新药理学。
