针对神经退行性疾病的蛋白水解靶向嵌合体研究进展

刘鹏, 曹端源, 罗金重, 谢赛赛, 刘婧

中国药学杂志 ›› 2023, Vol. 58 ›› Issue (19) : 1721-1730.

PDF(1146 KB)
中国药学杂志
PDF(1146 KB)
中国药学杂志 ›› 2023, Vol. 58 ›› Issue (19) : 1721-1730. DOI: 10.11669/cpj.2023.19.001
综述

针对神经退行性疾病的蛋白水解靶向嵌合体研究进展

  • 刘鹏a, 曹端源a, 罗金重a, 谢赛赛a*, 刘婧b*
作者信息 +

Progress in Research of PROTAC for Neurodegenerative Disorders Treatment

  • LIU Penga, CAO Duanyuana, LUO Jinchonga, XIE Saisaia*, LIU Jingb*
Author information +
文章历史 +

摘要

神经退行性疾病(neurodegenerative disorders,NDs)是一类引起神经细胞损伤或导致运动性、认知性功能障碍的疾病,其中一个最主要的病理特征为患者大脑中出现异常折叠的蛋白质聚集物,目前缺乏积极有效的药物用于NDs的治疗。而蛋白水解靶向嵌合体(proteolysis-targeting chimera, PROTAC)是一种双功能的小分子化合物,它可以将靶蛋白和E3泛素连接酶招募形成三元复合物,然后通过泛素蛋白酶体系统(ubiquitin-proteasome system, UPS)实现对靶蛋白的降解。理论上该技术有望靶向降解不可成药蛋白,因此在NDs研究中具有巨大潜力和发展空间,目前也受到了广泛关注。因此笔者对PROTAC技术进行了简要介绍,主要综述了其在NDs中的应用,并总结了PROTAC在NDs中应用的优势和挑战。

Abstract

Neurodegenerative disorders (NDs) are a class of diseases that cause neural cell damage or motor and cognitive dysfunction. One of the most important pathological features is the misfolded protein aggregates in the patient′s brain. There is currently a lack of active and effective drugs for the treatment of NDs. Proteolysis-targeting chimera(PROTAC) is a bifunctional small molecule compound, which can recruit the target protein and E3 ubiquitin ligase to form a ternary complex, and then degrade the target protein by the ubiquitin-proteasome system(UPS). Theoretically, it is expected to target and degrade undruggable proteins, so it has great potential and development space in the research of NDs, and it has also received extensive attention. This paper briefly introduces the PROTAC technology, mainly reviews its application in NDs, and summarizes the advantages and challenges of the application of PROTAC in NDs.

关键词

蛋白水解靶向嵌合体 / 神经退行性疾病 / 蛋白质降解 / 泛素-蛋白酶体系统 / 双功能分子

Key words

proteolysis-targeting chimera(PROTAC) / neurodegenerative disorders(NDs) / protein degradation / ubiquitin-proteasome system / bifunctional molecule

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用
刘鹏, 曹端源, 罗金重, 谢赛赛, 刘婧. 针对神经退行性疾病的蛋白水解靶向嵌合体研究进展[J]. 中国药学杂志, 2023, 58(19): 1721-1730 https://doi.org/10.11669/cpj.2023.19.001
LIU Peng, CAO Duanyuan, LUO Jinchong, XIE Saisai, LIU Jing. Progress in Research of PROTAC for Neurodegenerative Disorders Treatment[J]. Chinese Pharmaceutical Journal, 2023, 58(19): 1721-1730 https://doi.org/10.11669/cpj.2023.19.001
中图分类号： R945   

参考文献

[1] SAKAMOTO K M, KIM K B, KUMAGAI A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation . P Natl Acad Sci USA, 2001, 98(15):8554-8559.
[2] KONSTANTINIDOU M, LI J, ZHANG B, et al. PROTACs- a game-changing technology . Expert Opin Drug Discov, 2019, 14(12):1255-1268.
[3] YU S H, WANG X J, ZHENG X L, et al. Advances in proteolysis targeting chimeras . Chin Pharm J (中国药学杂志), 2021, 56(11):861-867.
[4] CHEN Y, JIN J. The application of ubiquitin ligases in the PROTAC drug design . Acta Biochim Biophys Sin, 2020, 52(7):776-790.
[5] SPASSER L, BRIK A. Chemistry and biology of the ubiquitin signal . Angew Chem Int Edit, 2012, 51(28):6840-6862.
[6] LIU B, ZHU Z J, TONG H J, et al. Research progress in proteolysis targeting chimeras based on small molecule E3 ubiquitin ligase adaptor . Chin Pharm J (中国药学杂志), 2022, 57(5):334-341.
[7] MORRISON C. Fresh from the biotech pipeline-2019 . Nat Biotechnol, 2020, 38(2):126-131.
[8] WISNIEWSKI T, GOÑI F. Immunotherapeutic Approaches for Alzheimer′s Disease . Neuron, 2015, 85(6):1162-1176.
[9] NIEWIDOK B, IGAEV M, SÜNDERMANN F, et al. Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau′s interaction with microtubules in axon-like processes . Mol Biol Cell, 2016, 27(22):3537-3549.
[10] DI J, COHEN L S, CORBO C P, et al. Abnormal tau induces cognitive impairment through two different mechanisms:synaptic dysfunction and neuronal loss . Sci Rep-UK, 2016, 6(1):20833. Doi: 10.1038/srep20833.
[11] K. IQBAL F L C X. Tau in Alzheimer Disease and Related Tauopathies . Curr Alzheimer Res, 2010, 7(8):656-664.
[12] ANDREA S, MOHAMED A. E, MOHAMED A R, et al. Dephosphorylation targeting chimaera (DEPTAC):targeting tau proteins in tauopathies . Curr Protein Pept Sci, 2022, 23(3):129-132.
[13] CHU T, GAO N, LI Q, et al. Specific knockdown of endogenous tau protein by peptide-directed ubiquitin-proteasome degradation . Cell Chem Biol, 2016, 23(4):453-461.
[14] LU M, LIU T, JIAO Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway . Eur J Med Chem, 2018, 146:251-259.
[15] LU M C, JI J A, JIANG Z Y, et al. The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update . Med Res Rev, 2016, 36(5):924-963.
[16] SILVA M C, FERGUSON F M, CAI Q, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models . eLife, 2019, 8:e45457. Doi: 10.7554/eLife.45457.
[17] SILVA M C, NANDI G, DONOVAN K A, et al. Discovery and optimization of Tau targeted protein degraders enabled by patient induced pluripotent stem cells-derived neuronal models of tauopathy . Front Cell Neurosci, 2022, 16:801179. Doi: 10.3389/fncel.2022.801179.
[18] WANG W, ZHOU Q, JIANG T, et al. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models . Theranostics, 2021, 11(11):5279-5295.
[19] CACACE A M, CHANDLER J, FLANAGAN J J, et al. O5-04-05:A new therapeutic strategy for tauopathies:discovery of highly potent brain penetrant protactm degrader molecules that target pathologic Tau protein species . Alzheimer′s Dementia, 2019, 15:P1624. DOI:10.1016/j.jalz.2019.06.4856.
[20] EMBI N, RYLATT D B, COHEN P. Glycogen synthase kinase-3 from rabbit skeletal muscle:Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase . Eur J Biochem, 1980, 107(2):519-527.
[21] WOODGETT J R. Molecular cloning and expression of glycogen synthase kinase-3/factor A . EMBO J, 1990, 9(8):2431-2438.
[22] HANSEN L, ARDEN K C, RASMUSSEN S B, et al. Chromosomal mapping and mutational analysis of the coding region of the glycogen synthase kinase-3α and β isoforms in patients with NIDDM . Diabetologia, 1997, 40(8):940-946.
[23] HARWOOD A J. Regulation of GSK-3:A Cellular Multiprocessor . Cell, 2001, 105(7):821-824.
[24] KAIDANOVICH-BEILIN O, WOODGETT J R. GSK-3:Functional insights from cell biology and animal models . Front Mol Neurosci, 2011, 4:40. Doi: 10.3389/fnmol.2011.00040.
[25] HOOPER C, KILLICK R, LOVESTONE S. The GSK3 hypothesis of Alzheimer′s disease . J Neurochem, 2008, 104(6):1433-1439.
[26] LEE S J, CHUNG Y H, JOO K M, et al. Age-related changes in glycogen synthase kinase 3β (GSK3β) immunoreactivity in the central nervous system of rats . Neurosci Lett, 2006, 409(2):134-139.
[27] JANKOWSKA A, SATALA G, BOJARSKI A J, et al. Multifunctional ligands with glycogen synthase kinase 3 inhibitory activity as a new direction in drug research for Alzheimer′s disease. Curr Med Chem, 2021, 28(9):1731-1745.
[28] DUKA T, DUKA V, JOYCE J N, et al. α-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson′s disease models . FASEB J, 2009, 23(9):2820-2830.
[29] L′EPISCOPO F, DROUIN-OUELLET J, TIROLO C, et al. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington′s disease:involvement of astrocyte-neuron interactions . Cell Death Dis, 2016, 7(4):e2206. Doi: 10.1038/cddis.2016.104.
[30] NOH M, CHUN K, KANG B Y, et al. Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer′s disease . Biochem Biophys Res Commun, 2013, 435(2):274-281.
[31] AVRAHAMI L, FARFARA D, SHAHAM-KOL M, et al. Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model:in vivo and in vitro studies . J Biol Chem, 2013, 288(2):1295-1306.
[32] KAIDANOVICH-BEILIN O, WOODGETT J R. GSK-3:Functional Insights from Cell Biology and Animal Models . Front Mol Neurosci, 2011, 4:40. Doi: 10.3389/fnmol.2011.00040.
[33] JIANG X, ZHOU J, WANG Y, et al. PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases . Eur J Med Chem, 2021, 210:112949. Doi: 10.1016/j.ejmech.2020.112949.
[34] QU L, LI S, JI L, et al. Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer′s disease . Eur J Med Chem, 2021, 226:113889. Doi: 10.1016/j.ejmech.2021.113889.
[35] COOKSON M R. LRRK2 pathways leading to neurodegeneration . Curr Neurol Neurosci, 2015, 15(7):42. Doi: 10.1007/s11910-015-0564-y.
[36] ZIMPRICH A, BISKUP S, LEITNER P, et al. Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology . Neuron, 2004, 44(4):601-607.
[37] DI MAIO R, HOFFMAN E K, ROCHA E M, et al. LRRK2 activation in idiopathic Parkinson′s disease . Sci Transl Med, 2018, 10(451):eaar5429. Doi: 10.1126/scitranslmed.aar5429.
[38] KARGBO R B. Degradation of LRRK2 in the Treatment of Parkinson′s Disease . ACS Med Chem Lett, 2020, 11(11):2070-2071.
[39] KONSTANTINIDOU M, OUN A, PATHAK P, et al. The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2) . Chem Med Chem, 2021, 16(6):959-965.
[40] LIU X, KALOGEROPULOU A F, DOMINGOS S, et al. Discovery of XL01126: a potent, fast, cooperative, selective, orally bioavailable, and blood-brain barrier penetrant PROTAC degrader of leucine-rich repeat kinase 2 . J Am Chem Soc, 2022 144(37):16930-16952.
[41] HELY M A, REID W G J, ADENA M A, et al. The Sydney multicenter study of Parkinson′s disease:The inevitability of dementia at 20 years . Mov Disord, 2008, 23(6):837-844.
[42] GIRI B, SEAMON M, BANERJEE A, et al. Emerging urinary alpha-synuclein and miRNA biomarkers in Parkinson′s disease . Metab Brain Dis, 2022, 37(6):1687-1696.
[43] CHENG F, VIVACQUA G, YU S. The role of alpha-synuclein in neurotransmission and synaptic plasticity . J Chem Neuroanat, 2011, 42(4):242-248.
[44] KARGBO R B. PROTAC compounds targeting α-synuclein protein for treating neurogenerative disorders: Alzheimer′s and parkinson′s diseases . ACS Med Chem Lett, 2020, 11(6):1086-1087.
[45] REINER A, DRAGATSIS I, DIETRICH P. Genetics and neuropathology of Huntington′s disease . Int Rev Neurobiol, 2011, 98:325-372.
[46] BATES G P, DORSEY R, GUSELLA J F, et al. Huntington disease . Nat Rev Dis Primers, 2015, 1(1):1-21.
[47] ROSS C A, POIRIER M A. Protein aggregation and neurodegenerative disease . Nat Med, 2004, 10(S7):S10-S17.
[48] LIU T, BITAN G. Modulating self-assembly of amyloidogenic proteins as a therapeutic approach for neurodegenerative diseases: strategies and mechanisms . Chem Med Chem, 2012, 7(3):359-374.
[49] TOMOSHIGE S, NOMURA S, OHGANE K, et al. Discovery of small molecules that induce the degradation of huntingtin . Angew Chem Int Ed Engl, 2017, 56(38):11530-11533.
[50] TOMOSHIGE S, NOMURA S, OHGANE K, et al. Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative . Bioorg Med Chem Lett, 2018, 28(4):707-710.
[51] YAMASHITA H, TOMOSHIGE S, NOMURA S, et al. Application of protein knockdown strategy targeting beta-sheet structure to multiple disease-associated polyglutamine proteins . Bioorg Med Chem, 2020, 28(1):115175. Doi: 10.1016/j.bmc.2019.115175.
[52] MAHGOUB M, MONTEGGIA L M. A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory . Learn Mem, 2014, 21(10):564-568.
[53] DE RUIJTER A J M, VAN GENNIP A H, CARON H N, et al. Histone deacetylases (HDACs):characterization of the classical HDAC family . Biochem J, 2003, 370(Part 3):737-749.
[54] SIMOES-PIRES C, ZWICK V, NURISSO A, et al. HDAC6 as a target for neurodegenerative diseases:what makes it different from the other HDACs? . Mol Neurodegener, 2013, 8:7. Doi: 10.1186/1750-1326-8-7.
[55] PENNEY J, TSAI L. Histone deacetylases in memory and cognition . Sci Signal, 2014, 7(355):e12. Doi: 10.1126/scisignal.aaa0069.
[56] SHEN S, KOZIKOWSKI A P. A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014-2019) . Expert Opin Ther Pat, 2020, 30(2):121-136.
[57] DING H, DOLAN P J, JOHNSON G V W. Histone deacetylase 6 interacts with the microtubule-associated protein tau . J Neurochem, 2008, 106(5):2119-2130.
[58] THOMAS E A, D′MELLO S R. Complex neuroprotective and neurotoxic effects of histone deacetylases . J Neurochem, 2018, 145(2):96-110.
[59] YANG K, SONG Y, XIE H, et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders . Bioorg Med Chem Lett, 2018, 28(14):2493-2497.
[60] WU H, YANG K, ZHANG Z, et al. Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity . J Med Chem, 2019, 62(15):7042-7057.
[61] YANG K, WU H, ZHANG Z, et al. Development of selective histone deacetylase 6 (HDAC6) degraders recruiting von hippel-lindau (VHL) E3 ubiquitin ligase . ACS Med Chem Lett, 2020, 11(4):575-581.
[62] AN Z, LV W, SU S, et al. Developing potent PROTACs tools for selective degradation of HDAC6 protein . Protein Cell, 2019, 10(8):606-609.
[63] YANG H, LV W, HE M, et al. Plasticity in designing PROTACs for selective and potent degradation of HDAC6 . Chem Commun, 2019, 55(98):14848-14851.
[64] KARGBO R B. Treatment of Cancer and Alzheimer′s Disease by PROTAC Degradation of EGFR . ACS Med Chem Lett, 2019, 10(8):1098-1099.
[65] KARGBO R B. PROTAC degradation of IRAK4 for the treatment of neurodegenerative and cardiovascular diseases . ACS Med Chem Lett, 2019, 10(9):1251-1252.
[66] WANG Y, JIANG X, FENG F, et al. Degradation of proteins by PROTACs and other strategies . Acta Pharm Sin B(药学学报 英文版), 2020, 10(2):207-238.
[67] EDMONDSON S D, YANG B, FALLAN C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space:Recent progress and future challenges . Bioorg Med Chem Lett, 2019, 29(13):1555-1564.
[68] FRANZMEIER N, NEITZEL J, RUBINSKI A, et al. Functional brain architecture is associated with the rate of tau accumulation in Alzheimer′s disease . Nat Commun, 2020, 11(1):347. Doi: 10.1038/s41467-019-14159-1.
[69] HIGGINS J J, TAL A L, SUN X, et al. Temporal and spatial mouse brain expression of cereblon, an ionic channel regulator involved in human intelligence . J Neurogenet, 2010, 24(1):18-26.
[70] THIBAUDEAU T A, ANDERSON R T, SMITH D M. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers . Nat Commun, 2018, 9(1):1097. Doi: 10.1038/s41467-018-03509-0.
[71] LV W X, HE M, RAO Y. Opportunities and challenges of small molecule targeted induced protein degradation technology . Chin J Med Chem(中国药物化学杂志), 2020, 30(12):745-764.

基金

国家自然科学基金项目资助(81760622,21807052);江西省科技创新杰出青年人才培养计划资助(20192BCB23018);江西省自然科学基金项目资助(20192ACBL21034,20202BAB216042);江西省教育厅项目资助(GJJ190673)
PDF(1146 KB)

Accesses

Citation

Detail
段落导航
相关文章

/

〈 〉