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α-芋螺毒素TxID异构体对人类乙酰胆碱受体的活性研究

长孙东亭, 朱晓鹏, 吴勇, 胡远艳, 邴晖, 罗素兰

长孙东亭, 朱晓鹏, 吴勇, 胡远艳, 邴晖, 罗素兰. α-芋螺毒素TxID异构体对人类乙酰胆碱受体的活性研究[J]. 中国药科大学学报, 2016, 47(4): 483-490. DOI: 10.11665/j.issn.1000-5048.20160416
引用本文: 长孙东亭, 朱晓鹏, 吴勇, 胡远艳, 邴晖, 罗素兰. α-芋螺毒素TxID异构体对人类乙酰胆碱受体的活性研究[J]. 中国药科大学学报, 2016, 47(4): 483-490. DOI: 10.11665/j.issn.1000-5048.20160416
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ZHANGSUN Dongting, ZHU Xiaopeng, WU Yong, HU Yuanyan, BING Hui, LUO Sulan. Activities of α-conotoxin TxID isomers on human nicotinic acetylcholine receptors[J]. Journal of China Pharmaceutical University, 2016, 47(4): 483-490. DOI: 10.11665/j.issn.1000-5048.20160416
Citation: ZHANGSUN Dongting, ZHU Xiaopeng, WU Yong, HU Yuanyan, BING Hui, LUO Sulan. Activities of α-conotoxin TxID isomers on human nicotinic acetylcholine receptors[J]. Journal of China Pharmaceutical University, 2016, 47(4): 483-490. DOI: 10.11665/j.issn.1000-5048.20160416
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α-芋螺毒素TxID异构体对人类乙酰胆碱受体的活性研究

  • 海南大学热带生物资源教育部重点实验室、海口市海洋药物重点实验室

基金项目: 国家自然科学基金重点国际合作项目资助(No.81420108028)；国家自然科学基金资助项目(No.41366002)；海口市重点科技计划项目资助(No.2013-16)；长江学者和创新团队发展计划资助项目(No.IRT-15R15)

Activities of α-conotoxin TxID isomers on human nicotinic acetylcholine receptors

摘要

    摘要
  • 摘要: 研究α-芋螺毒素TxID 3个二硫键异构体对人类α3β4与α6/α3β4乙酰胆碱受体的阻断活性。采用Fmoc固相合成法，分别合成α-芋螺毒素TxID的3个二硫键异构体的线性肽，利用2步氧化法进行氧化折叠，获得具有定点连接二硫键的异构体多肽。利用非洲爪蟾卵母细胞表达人类α3β4与α6/α3β4乙酰胆碱受体亚型，测定3个异构体对该乙酰胆碱受体的电流与洗脱速率的影响情况。α-芋螺毒素TxID的3个二硫键异构体对人类α3β4与α6/α3β4乙酰胆碱受体亚型的阻断活性差异很大，阻断是可逆的，洗脱速率较快。其中具有天然构象的球状异构体活性最强，其半数阻断剂量(IC50)仅约为9.3 nmol/L；其次是带状异构体具有很微弱的抑制活性，其IC50大于5 μmol/L；而珠子状异构体几乎没有阻断活性，其IC50大于10 μmol/L。成功合成了α-芋螺毒素TxID的3个二硫键异构体，并获知了3个二硫键异构体分别对人类α3β4与α6/α3β4乙酰胆碱受体亚型的阻断活性，为α-芋螺毒素TxID后续海洋新药研发提供理论基础。
    Abstract: To investigate activities of three isomers of α-conotoxin TxID on human α3β4 and α6/α3β4 nicotinic acetylcholine receptors(nAChRs). The three isomers of α-conotoxin TxID were synthesized using solid phase Fmoc chemistry and fully folded by two-step oxidations. Human α3β4 and α6/α3β4 nAChRs were expressed in oocytes of Xenopus laevis, which were used for bioassay of the three isomers, including inhibition and washout reversibility. There were obvious differences between the inhibition potency of each isomers at human α3β4 and α6/α3β4 nAChRs. The blocking was reversible and washout rapidly. The most potent isomer is the globular form with an IC50 of 9. 3 nmol/L on human α3β4 and α6/α3β4 nAChRs respectively. The 2nd potent isomer was the ribbon form with much less potency, which had an IC50 of > 5 μmol/L. The bead isomer had little or no block on human α3β4 and α6/α3β4 nAChRs with an IC50 of > 10 μmol/L. The three isomers of α-conotoxin TxID were synthesized successfully with two pairs of desired disulfide bond. Inhibition activities of the 3 isomers on human α3β4 and α6/α3β4 nAChRs were obtained respectively, which would be basis for new marine drug development of α-conotoxin TxID.
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  • [1] Gotti C,Clementi F.Neuronal nicotinic receptors:from structure to pathology[J].Prog Neurobiol,2004,74(6):363-396.
    [2] Gotti C,Moretti M,Bohr I,et al.Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer′s disease,Parkinson′s disease and dementia with Lewy bodies by immunoprecipitation[J].Neurobiol Dis,2006,23(2):481-489.
    [3] Lee CH,Huang CS,Chen CS,et al.Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells[J].J Natl Cancer Inst,2010,102(17):1322-1335.
    [4] Lee CH,Chang YC,Chen CS,et al.Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha9-nicotinic acetylcholine receptor expression in human breast cancer cells[J].Breast Cancer Res Treat,2011,129(2):331-345.
    [5] Rahman S. Nicotinic receptors as therapeutic targets for drug addictive disorders[J].CNS Neurol Disord Drug Targets,2013,12(5):633-640.
    [6] Azam L, McIntosh JM. Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors[J].Acta Pharmacol Sin,2009,30(6):771-783.
    [7] Olivera BM,Quik M,Vincler M,et al.Subtype-selective conopeptides targeted to nicotinic receptors:concerted discovery and biomedical applications[J].Channels(Austin),2008,2(2):143-152.
    [8] Lebbe E K,Peigneur S,Wijesekara I,et al.Conotoxins targeting nicotinic acetylcholine receptors:an overview[J].Mar Drugs,2014,12(5):2970-3004.
    [9] Luo S, Zhangsun D, Zhu X, et al. Characterization of a novel alpha-conotoxin TxID from Conus textile that potently blocks rat alpha3beta4 nicotinic acetylcholine receptors[J].J Med Chem,2013,56(23):9655-9663.
    [10] Azam L,McIntosh JM.Molecular basis for the differential sensitivity of rat and human alpha9alpha10 nAChRs to alpha-conotoxin RgIA[J].J Neurochem,2012,122(6):1137-1144.
    [11] Vincler M,Wittenauer S,Parker R,et al.Molecular mechanism for analgesia involving specific antagonism of alpha9 alpha10 nicotinic acetylcholine receptors[J].Proc Natl Acad Sci U S A,2006,103(47):17880-17884.
    [12] Halai R, Clark RJ, Nevin ST, et al. Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor[J].J Biol Chem,2009,284(30):20275-20284.
    [13] McIntosh JM,Azam L,Staheli S,et al.Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors[J].Mol Pharmacol,2004,65(4):944-952.
    [14] Wu Y,Wu X,Yu J,et al.Influence of disulfide connectivity on structure and bioactivity of alpha-conotoxin TxIA[J].Molecules,2014,19(1):966-979.
    [15] Dutton JL,Bansal PS,Hogg RC,et al.A new level of conotoxin diversity,a non-native disulfide bond connectivity in alpha-conotoxin AuIB reduces structural definition but increases biological activity[J].J Biol Chem,2002,277(50):48849-48857.
    [16] Jin AH,Brandstaetter H,Nevin ST,et al.Structure of alpha-conotoxin BuIA:influences of disulfide connectivity on structural dynamics[J].BMC Struct Biol,2007,7:28.
    [17] Gotti C, Clementi F, Fornari A, et al. Structural and functional diversity of native brain neuronal nicotinic receptors[J].Biochem Pharmacol,2009,78(7):703-711.
    [18] Nicke A,Wonnacott S,Lewis RJ.Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes[J].Eur J Biochem,2004,271(12):2305-2319.
    [19] Kasheverov IE,Utkin YN,Tsetlin VI.Naturally occurring and synthetic peptides acting on nicotinic acetylcholine receptors[J].Curr Pharm Des,2009,15(21):2430-2452.
    [20] Napier IA,Klimis H,Rycroft BK,et al.Intrathecal alpha-conotoxins Vc1.1,AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain[J].Neuropharmacology, 2012,62(7):2202-2207.
    [21] Blyth FM,March LM,Brnabic AJ,et al.Chronic pain in Australia:a prevalence study[J].Pain,2001,89(2/3):127-134.
    [22] Cousins MJ,Brennan F,Carr DB.Pain relief:a universal human right[J].Pain,2004,112(1/2):1-4.
    [23] Eisenberg E,McNicol ED,Carr DB.Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin:systematic review and meta-analysis of randomized controlled trials[J].JAMA,2005,293(24):3043-3052.
    [24] Improgo MR,Soll LG,Tapper AR,et al.Nicotinic acetylcholine receptors mediate lung cancer growth[J].Front Physiol,2013,4:251.
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  • 刊出日期:  2016-08-24

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