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化学进展 2014, Vol. 26 Issue (05): 889-897 DOI: 10.7536/PC131020 前一篇   后一篇

• 综述与评论 •

戈谢病的药物分子伴侣

李京, 谢小丽, 王佳佳, 王晓敏, 李静*, 王鹏*   

  1. 南开大学药学院和药物化学生物学国家重点实验室 天津化学化工协同创新中心 天津 300071
  • 收稿日期:2013-10-01 修回日期:2013-12-01 出版日期:2014-05-15 发布日期:2014-03-13
  • 通讯作者: 李静，e-mail：jinglink@nankai.edu.cn；王鹏，e-mail：pwang@nankai.edu.cn E-mail:jinglink@nankai.edu.cn；pwang@nankai.edu.cn
  • 基金资助:

    国家自然科学基金项目（No. 91013013，31000371）资助

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Small Molecular Pharmacological Chaperone for Gaucher Disease

Li Jing, Xie Xiaoli, Wang Jiajia, Wang Xiaomin, Li Jing*, Wang Peng*   

  1. College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Synergetic Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
  • Received:2013-10-01 Revised:2013-12-01 Online:2014-05-15 Published:2014-03-13
  • Supported by:

    The work was supported by the National Natural Science Foundation of China(No. 91013013, 31000371)

戈谢病（Gaucher disease，GD）是一种由于β-酸性葡萄糖脑苷脂酶（acid β-glucocerebrosidase，GCase）基因突变引起的常染色体隐性遗传疾病，也是发病率最高的溶酶体贮积病。突变GCase的内质网关联降解和靶向溶酶体运转受阻是主要病因。酶替代疗法（enzyme replacement therapy，ERT）和底物降低疗法（substrate reduction therapy，SRT）是临床采用的主要治疗方法，但只对未涉及神经病变的Ⅰ型GD有效，且存在体内稳定性差和难以透过血脑屏障等弊端。GCase酶竞争性抑制剂可在低浓度底物的胞质中与突变酶结合，诱导酶折叠和运转；在高浓度底物的溶酶体中与酶解离，释放酶分子。因此，基于竞争性抑制剂的药物分子伴侣（pharmacological chaperone，PC）成为最具前景的药物。结合本课题组对GCase PC的研究，本文介绍了GCase的结构、催化机理及目前GCase PC的研究进展。重点讨论了脱氧野尻霉素类、环己亚胺醇类、C-糖苷衍生物、氨基环醇类和双环类PC的构效关系，简单介绍了其他非糖来源的PC，最后展望了GCase PC的前景，指出了今后研究中的发展方向。

关键词： 戈谢病, β-葡萄糖脑苷脂酶, 药物分子伴侣

Gaucher disease (GD) is a human autosomal recessive disorder mainly due to mutations in the gene encoding for the lysosomal enzyme acid β-glucocerebrosidase (GCase). It is the most common lysosomal storage disorder. Endoplasmic reticulum associated degradation (ERAD) and limitation for translocation to lysosome are two main pathological factors for GD. So far, enzyme replcement therapy (ERT) and substrate reduction therapy (SRT) are approved medical treatments for type Ⅰ GD patients with non-neurological involvement. However, they are intrinsically associated with low stability in biological media as well as the impossibility to cross the blood brain barrier (BBB). GCase competitive inhibitors can bind mutant GCase in cytoplasm with low concentration substrates, induce it fold and translocate it to lysosome. In lysosome with high concentration substrates, competitive inhibitors dissociate from GCase and release it. Therefore, PCs (pharmacological chaperones) based on competitive inhibitors become the most promising drugs. According to the research on GCase PC in our group, the structure and the catalytic mechanism of GCase and related GCase PCs are introduced. Particularly, the structure and activity relationships of deoxynojirimycin, 1,5-dideoxy-1,5-imino-D-xylitol, isofagomine, aminoinositol and bicyclic iminosugar are discussed emphatically. In addition, other non-sugar derived PCs are briefly introduced. Finally, we analysize the future prospect of GCase PCs and propose the directions in development.

Contents
1 Introduction
2 Structure and catalytic mechanism of GCase
3 GCase pharmacological chaperones
3.1 Deoxynojirimycin
3.2 1,5-dideoxy-1,5-imino-D -xylitol
3.3 Isofagomine
3.4 Aminoinositol
3.5 Bicyclic iminosugar
3.6 Other non-sugar derived pharmacological chaperones
4 Conclusion and outlook

Key words: gaucher disease, acid β-glucocerebrosidase, pharmacological chaperone

中图分类号: 

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[1] Marco S, Michela P, Alberto R. Science, 2009, 325: 473.
[2] 江静雯(Jiang J W), 李晶(Li J), 刘文军(Liu W J). 生物工程学报(Chinese Journal of Biotechnology), 2011, 27(5): 724.
[3] 侯精飞(Hou J F), 叶新山(Ye X S). 中国科学:化学(Scientia Sinica Chimica), 2012, 42(12): 1732.
[4] Valverde A M, Reed S D, Schulman K A. Health Aff., 2012, 31(11): 2528.
[5] Aymami J, Barril X, Rodríguez-Pascau L, Martinell M. Pharm. Pat. Analyst., 2013, 1: 109.
[6] Hruska K S, LaMarca M E, Scott C R, Sidransky E. Hum. Mutat., 2008, 29: 567.
[7] Bendikov-Bar I, Horowitz M. Hum. Mutat., 2012, 33: 1398.
[8] Beutler E, Grabowsli G A. Gaucher disease. in The Metabolic and Molecular Based of Inherited Diseases. 8th ed. NY: McGraw-Hill, 2001. 3635.
[9] Suzuki Y, Ogawa S, Sakakibara Y. Perspect. Medicin. Chem., 2009, 3: 7.
[10] Hartl F U, Bracher A, Hayer-Hartl M. Nature, 2011, 475: 324.
[11] Boyd R E, Lee G, Rybczynski P, Benjamin E R, Khanna R, Wustman B A, Valencano K. J. Med. Chem., 2013, 56: 2705.
[12] Benito J M, García Fernández J M, Ortiz Mellet C. Expert. Opin. Ther. Pat., 2011, 6: 885.
[13] Dvir H, Harel M, McCarthy A A, Toker L, Silman I, Futerman A H, Sussman J. EMBO Reports, 2003, 7: 704.
[14] Brumshtein B, Greenblatt H M, Butters T D, Shaaltiel Y, Aviezer D, Silman I, Futerman A H, Sussman J L. J. Biol. Chem., 2007, 39: 29052.
[15] Sawkar A R, Cheng W C, Beutler E, Wong C H, Balch W E, Kelly J W. Proc. Natl. Acad. Sci. U. S. A., 2002, 24: 15428.
[16] Sawkar A R, Adamski-Werner S L, Cheng W C, Wong C H, Beutler E, Zimmer K P, Kelly J W. Chem. Biol., 2006, 4: 235.
[17] Trapero A, Llebaria A. Future. Med. Chem., 2013, 5(5): 573.
[18] Sawkar A R, Adamski-Werner S L, Cheng W C, Wong C H, Beutler E, Zimmer K P, Kelly J W. Chem. Biol., 2005, 12: 1235.
[19] Mellor H R, Platt F M, Dwek R A, Butters T D. Biochem. J., 2003, 374: 307.
[20] Frohlich R E G, Furneaux R H, Mahuran D J, Rigat B A, Stuzu A E, Tropak M B, Wicki J, Withers S G, Wrodnigg T M. Carbohydr. Res., 2010, 345: 1371.
[21] Doit J D, Moreno I G, Twigg G, Ortiz M C, Haupt K, Butters T D, Kovensky J, Gouin S G. J. Org. Chem., 2011, 76: 7757.
[22] Cheng W C, Weng C Y, Yun W Y, Chang S Y, Lin Y C, Tasi F J, Huang F Y, Chen Y R. Bioorg. Med. Chem., 2013, 21: 5021.
[23] Yu L, Ikeda K, Kato A, Adachi I, Godin G, Compain P, Martin O, Asano N. Bioorg. Med. Chem., 2006, 14: 7736.
[24] Wang G N, Reinkensmeier G, Zhang S W, Zhou J, Zhang L R, Zhang L H, Butters D, Ye S. J. Med. Chem., 2009, 52: 3146.
[25] Wang G N Twigg G, Butters T D, Zhang S, Zhang L, Zhang L H, Ye X S. Org. Biomol. Chem., 2012, 10: 2923.
[26] Compain P, Martin O R, Boucheron C, Godin G, Yu L, Ikeda K, Asano N. ChemBioChem., 2006, 7: 1356.
[27] Goddard-Borger E D, Tropak M B, Yonekawa S, Tysoe C, Mahuran D J, Withers S G. J. Med. Chem., 2012, 55: 2737.
[28] Chang H H, Asano N, Ishii S, Ichikawa Y, Fan J Q. FEBS. J., 2006, 273: 4082.
[29] Khanna R, Benjamin E R, Pellegrino L, Schilling A, Rigat B A, Soska R, Nafar H, Ranes B E, Feng J, Lun Y, Powe A C, Palling D J, Wustman B A, Schiffmann R, Mahuran D J, Lockhart D J, Valenzano K J. FEBS. J., 2010, 277: 1618.
[30] Steet R A, Chung S, Wustman B, Powe A, Do H, Kornfeld S A. Proc. Natl. Acad. Sci. U. S. A., 2006, 37: 13813.
[31] Steet R, Chung S, Lee W S, Pine C W, Do H, Kornfeld S. Biochem. Pharmacol., 2007, 73: 1376.
[32] Lieberman R L, Wustman B A, Huertas P, Powe A C Jr, Pine C W, Khanna R, Schlossmacher M G, Ringe D, Petsko G A. Nat. Chem. Biol., 2006, 3(2): 101.
[33] Amicus Therapeutics.[2011-2-11] http://www.amicustherapeutics. com/clinicaltrials
[34] Zhu X, Sheth K A, Li S, Chang H H, Fan J Q. Angew. Chem. Int. Ed., 2005, 44(45): 7450.
[35] Amicus T. WO 2005046612, 2005
[36] Ogawa S, Ashiura M, Uchida C, Watanabe S, Yamazaki C, Yamagishi K, Inokuchi J I. Bio. Med. Chem. Lett., 199, 6(8): 929.
[37] Yu Z, Sawkar A R, Whalen L J, Wong C H, Kelly J W. J. Med. Chem., 2007, 50: 94.
[38] Lei K, Ninomiya H, Suzuki M, Inoue T, Sawa M, Iida M, Ida H, Eto Y, Ogawa S, Ohno K, Suzuki Y. Biochim. Biophys. Acta, 2007, 1772: 587.
[39] Luan Z, Ninomiya H, Ohno K, Ogawa S, Kubo T, Iida M, Suzuki Y. Brain and Development, 2010, 32(10), 805.
[40] Trapero A, González-Bulnes P, Butters T D, Llebaria A J. Med. Chem., 2012, 55: 4479.
[41] Díaz L, Bujons J, Casas J, Llebaria A, Delgado A. J. Med. Chem., 2010, 53: 5248.
[42] Díaz L, Casas J, Bujons J, Llebaria A, Delgado A. J. Med. Chem., 2011, 54: 2069.
[43] Díaz P, Garcia M, Ortiz M, Fuentes J, Díaz A, Javier C, Garcia F. J. Org. Chem., 2000, 65: 136.
[44] Trapero A, Llebaria A. Med. Chem. Lett., 2011, 2: 614.
[45] Trapero A, Alfonso I, Butters TD, Llebaria A. J. Am. Chem. Soc., 2011, 133: 5474.
[46] Castilla J, Rísquez R, Cruz D, Higaki K, Nanba E, Ohno K, Suzuki Y, Díaz Y, Ortiz Mellet C, García Fernández J M, Castillón S. J. Med. Chem., 2012, 55: 6857.
[47] Li Z, Li T, Dai S, Xie X, Ma X, Zhao W, Zhang W, Li J, Wang P G. ChemBioChem., 2013, 14(10):1239.
[48] Maegawa G H, Tropak M B, Buttner J D, Rigat B A, Fuller M, Pandit D, Tang L, Kornhaber G J, Hamuro Y, Clarke J T, Mahuran D J. J. Bio. Chem., 2009, 284: 23502.
[49] Mahuran D J, Tropak M B, Buttner J D. WO 2009049421, 2009.
[50] Tropak M B, Kornhaber G J, Rigat B A, Maegawa G H, Buttner J D, Blanchard J E, Murphy C, Tuske S J, Coales S J, HamuroY, Brown E D, Mahuran D J. ChemBioChem., 2008, 9: 2650.
[51] Zheng W, Padia J, Urban D J, Jadhav A, Goker-Alpan O, Simeonov A, Goldin E, Auld D, Lamarca M E, Inglese J, Austin C P, Sidransky E. Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 13192.
[52] Marugan J J, Zheng W, Motabar O, Southall N, Goldin E, Westbroek W, Stubblefield B K, Sidransky E, Aungst R A, Lea W A, Simeonov A, Leister W, Austin C P. J. Med. Chem., 2011, 54: 1033.
[53] Patnaik S, Zheng W, Choi J H, Motabar O, Southall N, Westbroek W, Lea W A, Velayati A, Goldin E, Sidransky E, Leister W, Marugan J J. J. Med. Chem., 2012, 55(12): 5734.
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摘要

戈谢病的药物分子伴侣