Zhang Baojian, Ren Maomao, Xiong Yang, Li Haonan, Wu Yong, Fu Ying, Zhangsun Dongting, Dong Shuai, Luo Sulan
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.
Medical School, Guangxi University, Nanning 530004, China.
Mar Drugs. 2021 Feb 22;19(2):119. doi: 10.3390/md19020119.
α-Conotoxin TxIB, a selective antagonist of α6/α3β2β3 nicotinic acetylcholine receptor, could be a potential therapeutic agent for addiction and Parkinson's disease. As a peptide with a complex pharmacophoric conformation, it is important and difficult to find a modifiable site which can be modified effectively and efficiently without activity loss. In this study, three xylene scaffolds were individually reacted with one pair of the cysteine residues ([1,3] or [2,4]), and iodine oxidation was used to form a disulfide bond between the other pair. Overall, six analogs were synthesized with moderate isolated yields from 55% to 65%, which is four times higher than the traditional two-step oxidation with orthogonal protection on cysteines. The cysteine [2,4] modified analogs, with higher stability in human serum than native TxIB, showed obvious inhibitory effect and selectivity on α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs), which was 100 times more than the cysteine [1,3] modified ones. This result demonstrated that the cysteine [2,4] disulfide bond is a new modifiable site of TxIB, and further modification can be a simple and feasible strategy for the exploitation and utilization of α-Conotoxin TxIB in drug discovery.
α-芋螺毒素TxIB是α6/α3β2β3烟碱型乙酰胆碱受体的选择性拮抗剂，可能是治疗成瘾和帕金森病的潜在药物。作为一种具有复杂药效构象的肽，找到一个可有效修饰且不会导致活性丧失的可修饰位点既重要又困难。在本研究中，将三种二甲苯支架分别与一对半胱氨酸残基（[1,3]或[2,4]）反应，并利用碘氧化在另一对半胱氨酸残基之间形成二硫键。总体而言，合成了六个类似物，分离产率适中，为55%至65%，比传统的对半胱氨酸进行正交保护的两步氧化法高出四倍。半胱氨酸[2,4]修饰的类似物在人血清中的稳定性高于天然TxIB，对α6/α3β2β3烟碱型乙酰胆碱受体（nAChRs）表现出明显的抑制作用和选择性，是半胱氨酸[1,3]修饰类似物的100倍。该结果表明，半胱氨酸[2,4]二硫键是TxIB的一个新的可修饰位点，进一步修饰可能是在药物研发中开发和利用α-芋螺毒素TxIB的一种简单可行的策略。
