促通读药物的作用机制与临床应用

doi:10.16288/j.yczz.15-519

遗传 ›› 2016, Vol. 38 ›› Issue (7): 623-633.doi: 10.16288/j.yczz.15-519

促通读药物的作用机制与临床应用

付洋, 舒在悦, 顾鸣敏

上海交通大学医学院,上海 200025

收稿日期:2015-12-24 出版日期:2016-07-20 发布日期:2016-07-20
作者简介:付洋,2014级临床医学专业4+4学生,专业方向：临床医学。E-mail: fuyang19920114@sina.com
基金资助:
国家自然科学基金项目(编号：30470951,31071107,31571295)资助[Supported by the National Natural Science of China (Nos; 30470951,31071107,31571295)]

The functional mechanisms and clinical application of read-through drugs

Yang Fu, Zaiyue Shu, Mingmin Gu

School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China

Received:2015-12-24 Online:2016-07-20 Published:2016-07-20

摘要/Abstract

摘要： 据统计,全球有近1/10的遗传病由无义突变(Nonsense mutation)所致。无义突变通常导致翻译提前终止,生成截短的、无功能的蛋白质。近年来,促通读药物在无义突变所致遗传病的治疗方面取得了明显进展。然而,由于翻译终止的机制仍不甚明了,因此促通读药物的机制研究和临床应用面临着新的挑战。本文主要探讨了促通读药物治疗无义突变所致遗传病的作用机制,以及促通读药物在临床应用方面的研究进展、存在的问题及应对策略。

关键词: 遗传病, 无义突变, 促通读药物, 作用机制, 临床应用

Abstract: According to previous reports, nearly one in 10 genetic diseases are caused by nonsense mutations around the world. Nonsense mutations lead to premature transcription terminations in cells, which in turn generate non-functional, truncated proteins. In recent years, read-through drugs are playing increasing prominent roles in the researches related to genetic diseases caused by nonsense mutations. However, due to the fact that the mechanisms lying behind translation termination still remain to be elucidated, the mechanistic research and clinical application of read-through drugs are facing new challenges. This review mainly discusses about the pathogenesis of genetic diseases caused by nonsense mutations, and then introduces the current clinical application of read-through drugs. Finally, we display some problems that remain to be solved and propose some possible coping strategies.

Key words: genetic disease, nonsense mutation, read-through drug, functional mechanism, clinical application

付洋, 舒在悦, 顾鸣敏. 促通读药物的作用机制与临床应用[J]. 遗传, 2016, 38(7): 623-633.

Yang Fu, Zaiyue Shu, Mingmin Gu. The functional mechanisms and clinical application of read-through drugs[J]. HEREDITAS(Beijing), 2016, 38(7): 623-633.

参考文献

[1] Keeling KM, Bedwell DM. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdiscip Rev RNA , 2011, 2(6): 837-852.
[2] Bidou L, Allamand V, Rousset JP, Namy O. Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med , 2012, 18(11): 679-688.
[3] Lee HLR, Dougherty JP. Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther , 2012, 136(2): 227-266.
[4] 乔中东. 分子生物学. 北京: 军事医学科学出版社, 2012.
[5] Zhouravleva G, Frolova L, Le Goff X, Le Guellec R, Inge-Vechtomov S, Kisselev L, Philippe M. Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. EMBO J , 1995, 14(16): 4065-4072.
[6] Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med , 1996, 2(4): 467-469.
[7] Fearon K, McClendon V, Bonetti B, Bedwell DM. Premature translation termination mutations are efficiently suppressed in a highly conserved region of yeast Ste6p, a member of the ATP-binding cassette (ABC) transporter family. J Biol Chem , 1994, 269(27): 17802-17808.
[8] Wohlgemuth I, Pohl C, Mittelstaet J, Konevega AL, Rodnina MV. Evolutionary optimization of speed and accuracy of decoding on the ribosome. Philos Trans R Soc Lond B Biol Sci , 2011, 366(1580): 2979-2986.
[9] Keeling KM, Wang D, Conard SE, Bedwell DM. Suppression of premature termination codons as a therapeutic approach. Crit Rev Biochem Mol Biol , 2012, 47(5): 444-463.
[10] Ogle JM, Murphy FV, Tarry MJ, Ramakrishnan V. Selection of tRNA by the ribosome requires a transition from an open to a closed form. Cell , 2002, 111(5): 721-732.
[11] Demeshkina N, Jenner L, Westhof E, Yusupov M, Yusupova G. A new understanding of the decoding principle on the ribosome. Nature , 2012, 484(7393): 256-259.
[12] Laurberg M, Asahara H, Korostelev A, Zhu JY, Trakhanov S, Noller HF. Structural basis for translation termination on the 70S ribosome. Nature , 2008, 454(7206): 852-857.
[13] Fan-Minogue H, Bedwell DM. Eukaryotic ribosomal RNA determinants of aminoglycoside resistance and their role in translational fidelity. RNA , 2008, 14(1): 148-157.
[14] Keeling KM, Brooks DA, Hopwood JJ, Li PN, Thompson JN, Bedwell DM. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet , 2001, 10(3): 291-299.
[15] Amrani N, Ganesan R, Kervestin S, Mangus DA, Ghosh S, Jacobson A. A faux 3'-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature , 2004, 432(7013): 112-118.
[16] Hoshino S, Imai M, Kobayashi T, Uchida N, Katada T. The eukaryotic polypeptide chain releasing factor (eRF3/ GSPT) carrying the translation termination signal to the 3'-Poly(A) tail of mRNA. Direct association of erf3/GSPT with polyadenylate-binding protein. J Biol Chem , 1999, 274(24): 16677-16680.
[17] Du M, Keeling KM, Fan LM, Liu XL, Kovacs T, Sorscher E, Bedwell DM. Clinical doses of amikacin provide more effective suppression of the human CFTR -G542X stop mutation than gentamicin in a transgenic CF mouse model. J Mol Med (Berl) , 2006, 84(7): 573-582.
[18] Howard MT, Anderson CB, Fass U, Khatri S, Gesteland RF, Atkins JF, Flanigan KM. Readthrough of dystrophin stop codon mutations induced by aminoglycosides. Ann Neurol , 2004, 55(3): 422-426.
[19] Wang D, Belakhov V, Kandasamy J, Baasov T, Li SC, Li YT, Bedwell DM, Keeling KM. The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse. Mol Genet Metab , 2012, 105(1): 116-125.
[20] Malik V, Rodino-Klapac LR, Viollet L, Wall C, King W, Al-Dahhak R, Lewis S, Shilling CJ, Kota J, Serrano- Munuera C, Hayes J, Mahan JD, Campbell KJ, Banwell B, Dasouki M, Watts V, Sivakumar

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促通读药物的作用机制与临床应用

The functional mechanisms and clinical application of read-through drugs

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