免疫化学专刊

C2H2锌指蛋白药物递送技术的研发与应用

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  • 上海科技大学 免疫化学研究所,上海 201210

收稿日期: 2021-06-19

  网络出版日期: 2021-10-22

Development and application of C2H2 zinc finger protein-based drug delivery technology

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  • Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China

Received date: 2021-06-19

  Online published: 2021-10-22

摘要

锌指蛋白是真核生物中广泛存在的转录因子,在基因的表达调控中起着重要作用。近期研究发现,C2H2类型的锌指蛋白(通过两个半胱氨酸和两个组氨酸螯合锌离子)可通过巨胞饮进入哺乳动物细胞。进一步的研究发现C2H2锌指蛋白可介导多种模式蛋白质及药物蛋白质的高效细胞递送,其细胞穿透效率亦高于传统的细胞穿膜肽。文章介绍了锌指蛋白的基本生物学信息和其细胞穿透特性,并讨论C2H2 锌指蛋白在大分子药物递送中的应用。

本文引用格式

李璐, 魏旋, 刘佳 . C2H2锌指蛋白药物递送技术的研发与应用[J]. 自然杂志, 2021 , 43(5) : 359 -364 . DOI: 10.3969/j.issn.0253-9608.2021.05.006

Abstract

Zinc finger proteins (ZFPs) are widespread transcription factors in eukaryotes and play important roles in gene expression
regulation. Recent studies have shown that C2H2 ZFPs can penetrate mammalian cells through macropinocytosis. In further studies, we have found that C2H2 ZFPs are capable of achieving highly efficient cellular delivery of a wide range of proteins including both reporter proteins and therapeutic proteins, with superior cell-penetrating activity to traditional cell-penetrating peptides (CPPs). In this review, we introduce the basic biology and the cell-penetrating activities of ZFPs, and discuss the application of C2H2 ZFPs in macromolecular drug delivery.

参考文献

[1] VALLEE B L, FALCHUK K H. The biochemical basis of zinc physiology [J]. Physiol Rev, 1993, 73: 79-118. 

[2] FRANKEL A D, PABO C O. Fingering too many proteins [J]. Cell, 1988, 53: 675. 

[3] BERG J M, SHI Y. The galvanization of biology: a growing appreciation for the roles of zinc [J]. Science, 1996, 271: 1081- 1085.

[4] HARRISON S C. A structural taxonomy of DNA-binding domains [J]. Nature, 1991, 353: 715-719. 

[5] COX D B, PLATT R J, ZHANG F. Therapeutic genome editing: prospects and challenges [J]. Nat Med, 2015, 21: 121-131. 

[6] KIM Y G, CHA J, CHANDRASEGARAN S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain [J]. PNAS, 1996, 93: 1156-1160. 

[7] GERSBACH C A, GAJ T, BARBAS C F, et al. Synthetic zinc finger proteins: the advent of targeted gene regulation and genome modification technologies [J]. Acc Chem Res, 2014, 47: 2309-2318. 

[8] TEBAS P, STEIN D, TANG W W. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV [J]. N Engl J Med, 2014, 370: 901-910. 

[9] GAJ T, GUO J, KATO Y. et al. Targeted gene knockout by direct delivery of zinc-finger nuclease proteins [J]. Nat Methods, 2012, 9: 805-807. 

[10] LIU J, GAJ T, PATTERSON J T, et al. Cell-penetrating peptidemediated delivery of TALEN proteins via bioconjugation for genome engineering [J]. PLoS One, 2014, 9: e85755. 

[11] KIM S, KIM D, CHO S W, et al. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins [J]. Genome Res, 2014, 24: 1012-1019. 

[12] GAJ T, LIU J, ANDERSON K E, et al. Protein delivery using Cys2- His2 zinc-finger domains [J]. ACS Chem Bio, 2014, 9: 1662-1667. 

[13] LIU J, SHUI S L. Delivery methods for site-specific nucleases: Achieving the full potential of therapeutic gene editing [J]. J Control Release, 2016, 244: 83-97. 

[14] GILLMEISTER M P, BETENBAUGH M J, FISHMAN P S. Cellular trafficking and photochemical internalization of cell penetrating peptide linked cargo proteins: a dual fluorescent labeling study [J]. Bioconjug Chem, 2011, 22: 556-566. 

[15] MAI J C, SHEN H, WATKINS S C, et al. Efficiency of protein transduction is cell type-dependent and is enhanced by dextran sulfate [J]. Biochem J, 2002, 277: 30208-30218. 

[16] LINDSAY M A. Peptide-mediated cell delivery: application in protein target validation [J]. Curr Opin Biotechnol, 2002, 2: 587- 594. 

[17] VANDENBERG A, DOWDY S F. Protein transduction domain delivery of therapeutic macromolecules [J]. Curr Opin Biotechnol, 2011, 22: 888-893. 

[18] KOREN E, TORCHILIN V P. Cell-penetrating peptides: breaking through to the other side [J]. Trends Mol Med, 2012, 18: 385-393. 

[19] LIU J, GAJ T, WALLEN M C, et al. Improved cell-penetrating zincfinger nuclease proteins for precision genome engineering [J]. Mol Ther Nucleic Acids, 2015, 4: e232. 

[20] PANG X, TONG Y, LI F, et al. Expression and characterization of human lactoferrin with tandem zinc finger protein in Chlamydomonas reinhardtii [J]. Algal Res, 2019, 43: 101635. 

[21] SUZUKI Y A, LOPEZ V, LONNERDAL B. Mammalian lactoferrin receptors: structure and function [J]. Cell Mol Life Sci, 2005, 62: 2560-2575. 

[22] SALVEMINI D, RILEY D P, CUZZOCREA S. SOD mimetics are coming of age [J]. Nat Rev Drug Discov, 2002, 1: 367-374. 

[23] FRIDOVICH I. Superoxide radical and superoxide dismutases [J]. Annu Rev Biochem, 1995, 64: 97-112.

[24] MCCORD J M. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase [J]. Science, 1974, 185: 529- 531. 

[25] YANG G, CHAN P H, CHEN J, et al. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia [J]. Stroke, 1994, 25: 165-170. 

[26] LAND W, ZWELER J L. Prevention of reperfusion-induced, free radical-mediated acute endothelial injury by superoxide dismutase as an effective tool to delay/prevent chronic renal allograft failure: a review [J]. Transplant Proc, 1997, 29: 2567-2568.

 [27] SHINGU M, TAKAHASHI S, ITO M, et al. Anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis in rats [J]. Rheumatol Int, 1994, 14: 77-81. 

[28] LAZZARI F D, BUBACCO L, WHITWORTH A J, et al. Superoxide radical dismutation as new therapeutic strategy in parkinson’s disease [J]. Aging Dis, 2018, 9: 716-728. 

[29] SAFFORD S E, OBERLEY T D, URANO M, et al. Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase [J]. Cancer Res, 1994, 54: 4261-4265. 

[30] CHURCH S L, GRANT J W, RIDNOUR L A, et al, Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells [J]. PNAS, 1993, 90: 3113-3117. 

[31] MOLLACE V, NOTTET H S, CLAYETTE P, et al. Oxidative stress and neuroAIDS: triggers, modulators and novel antioxidants [J]. Trends Neurosci, 2001, 24: 411-416. [32] LIU J, LI J, LI J, et al. Delivery of superoxide dismutase using Cys2- His2 zinc-finger proteins [J]. Methods Mol Biol, 2018, 1867: 113- 123.

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