Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences , Hainan University , Haikou 570228 , China.
Institute for Molecular Bioscience , The University of Queensland , Brisbane , Queensland 4072 , Australia.
J Med Chem. 2020 Feb 27;63(4):1564-1575. doi: 10.1021/acs.jmedchem.9b01409. Epub 2020 Feb 7.
αO-conotoxin GeXIVA from 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 IC 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.
来自 的αO-芋螺毒素 GeXIVA 是一种有效的α9α10 nAChR 拮抗剂，在疼痛动物模型中具有镇痛作用。该肽具有两个二硫键交联，珠状和带状异构体对α9α10 nAChRs 具有相似的抑制活性。我们合成了 12 个珠状 GeXIVA 的二硫键缺陷类似物，所有类似物仍然是α9α10 nAChR 的有效抑制剂。最有效的二硫键缺陷类似物在大鼠和人α9α10 nAChRs 上的 IC 值分别为 6 和 33 nM，与珠状 GeXIVA 相比，增加不到 2 倍。根据 NMR 光谱，二硫键缺陷类似物和母体肽也没有明确的结构。分子模拟表明，GeXIVA 的二硫键和末端与受体没有建立稳定的相互作用。总的来说，这项研究表明，通过二硫键缺失和潜在的末端截断，可以简化镇痛肽 GeXIVA 的结构。
