Structure and Activity Studies of Disulfide-Deficient Analogues of αO-Conotoxin GeXIVA.,Journal of Medicinal Chemistry

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Structure and Activity Studies of Disulfide-Deficient Analogues of αO-Conotoxin GeXIVA.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-27 , DOI: 10.1021/acs.jmedchem.9b01409
Pan Xu ₁ , Quentin Kaas ₂ , Yong Wu ₁ , Xiaopeng Zhu ₁ , Xincan Li ₁ , Peta J Harvey ₂ , Dongting Zhangsun ₁ , David J Craik ₂ , Sulan Luo ₁

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αO-conotoxin GeXIVA from Conus generalis is a potent antagonist of the α9α10 nAChR and analgesic in animal models of pain. This peptide has two disulfide bond cross-links, and the bead and ribbon isomers have similar inhibitory activity against α9α10 nAChRs. We synthesized 12 disulfide-deficient analogues of bead GeXIVA, and all remained potent inhibitors of α9α10 nAChR. The most potent disulfide-deficient analogue displayed IC50 values of 6 and 33 nM at rat and human α9α10 nAChRs, respectively, representing less than a 2-fold increase compared with bead GeXIVA. The disulfide-deficient analogs and parent peptides also do not have a well-defined structure according to NMR spectroscopy. Molecular simulations suggest that the disulfide bonds and termini of GeXIVA do not establish stable interactions with the receptor. Overall, this study proposes that the structure of the analgesic peptide GeXIVA could be simplified through disulfide bond deletions and potentially termini truncations.

中文翻译：

αO-芋螺毒素GeXIVA缺乏二硫键的类似物的结构和活性研究。

来自Conus generalis的αO-芋螺毒素GeXIVA是α9α10nAChR的有效拮抗剂，在动物疼痛模型中具有镇痛作用。该肽具有两个二硫键交联键，并且珠和带状异构体对α9α10nAChRs具有相似的抑制活性。我们合成了珠GeXIVA的12种缺乏二硫键的类似物，所有这些都是α9α10nAChR的有效抑制剂。最有效的二硫键缺乏类似物在大鼠和人α9α10nAChRs处的IC50值分别为6和33 nM，与GeXIVA磁珠相比，增加不到2倍。根据NMR光谱，缺乏二硫化物的类似物和母体肽也没有明确的结构。分子模拟表明，GeXIVA的二硫键和末端不能与受体建立稳定的相互作用。总体，

更新日期：2020-02-07

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