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Recent advances in DNAzyme-based gene silencing

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Abstract

DNAzymes, generated through in vitro selection processes, are single-stranded DNA catalysts that can catalyze a wide variety of reactions, such as RNA or DNA cleavage and ligation or DNA phosphorylation. Based on specific cofactor dependence and potent catalytic ability, DNAzymes have been extensively used to develop highly sensitive and specific sensing platforms for metal ions, small molecules, and biomacromolecules. However, in spite of their multiple strong enzymatic turnover properties, few reports have addressed the potential application of RNA-cleaving DNAzymes as therapeutic gene-silencing agents. The main challenges are being met with low efficiency of cellular uptake, instability and the lack of sufficient cofactors for cellular or in vivo study, which have limited the development of DNAzymes for clinical application. In recent years, substantial progress has been made to enhance the delivery efficiency and stability of DNAzymes by developing variety of methods. Smart metal oxide nanomaterials have also been used to meet the requirement of cofactors in situ. This review focuses on the gene silencing application of DNAzymes as well as their physicochemical properties. Methods of increasing the efficacy of DNAzymes in gene therapy are also discussed: delivery systems to enhance the cellular uptake, modifications to enhance the stability and smart systems to generate sufficient cofactors in situ. Finally, some future trends and perspectives in these research areas are outlined.

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References

  1. Liu J, Cao Z, Lu Y. Chem Rev, 2009, 109: 1948–1998

    Article  CAS  Google Scholar 

  2. Breaker RR, Joyce GF. Chem Biol, 1994, 1: 223–229

    Article  CAS  Google Scholar 

  3. Silverman SK. Acc Chem Res, 2009, 42: 1521–1531

    Article  CAS  Google Scholar 

  4. Endo M, Takeuchi Y, Suzuki Y, Emura T, Hidaka K, Wang F, Willner I, Sugiyama H. Angew Chem, 2015, 127: 10696–10700

    Article  Google Scholar 

  5. Hwang K, Wu P, Kim T, Lei L, Tian S, Wang Y, Lu Y. Angew Chem Int Ed, 2014, 53: 13798–13802

    Article  CAS  Google Scholar 

  6. Liu J, Lu Y. J Am Chem Soc, 2003, 125: 6642–6643

    Article  CAS  Google Scholar 

  7. Yin BC, Ye BC, Tan W, Wang H, Xie CC. J Am Chem Soc, 2009, 131: 14624–14625

    Article  CAS  Google Scholar 

  8. Wu P, Hwang K, Lan T, Lu Y. J Am Chem Soc, 2013, 135: 5254–5257

    Article  CAS  Google Scholar 

  9. Elbaz J, Shlyahovsky B, Willner I. Chem Commun, 2008, 1569–1571

    Google Scholar 

  10. Yang C, Lates V, Prieto-Simón B, Marty JL, Yang X. Biosens Bioelectron, 2012, 32: 208–212

    Article  CAS  Google Scholar 

  11. Zhang XB, Wang Z, Xing H, Xiang Y, Lu Y. Anal Chem, 2010, 82: 5005–5011

    Article  CAS  Google Scholar 

  12. Lu LM, Zhang XB, Kong RM, Yang B, Tan W. J Am Chem Soc, 2011, 133: 11686–11691

    Article  CAS  Google Scholar 

  13. Dass CR, Choong PF, Khachigian LM. Mol Cancer Ther, 2008, 7: 243–251

    Article  CAS  Google Scholar 

  14. Xu ZJ, Yang LF, Sun LQ, Cao Y. Chin Sci Bull, 2012, 57: 3404–3408

    Article  CAS  Google Scholar 

  15. Santoro SW, Joyce GF. Proc Natl Acad Sci USA, 1997, 94: 4262–4266

    Article  CAS  Google Scholar 

  16. Dass CR, Choong PFM. Oligonucleotides, 2010, 20: 51–60

    Article  CAS  Google Scholar 

  17. Akhtar S, Hughes MD, Khan A, Bibby M, Hussain M, Nawaz Q, Double J, Sayyed P. Adv Drug Deliver Rev, 2000, 44: 3–21

    Article  CAS  Google Scholar 

  18. Ruble BK, Richards JL, Cheung-Lau JC, Dmochowski IJ. Inorg Chim Acta, 2012, 380: 386–391

    Article  CAS  Google Scholar 

  19. Cieslak M, Szymanski J, Adamiak RW, Cierniewski CS. J Biol Chem, 2003, 278: 47987–47996

    Article  CAS  Google Scholar 

  20. Ellington AD, Szostak JW. Nature, 1990, 346: 818–822

    Article  CAS  Google Scholar 

  21. Beaudry AA, Joyce GF. Science, 1992, 257: 635–641

    Article  CAS  Google Scholar 

  22. Cairns MJ. Nucleic Acids Res, 2003, 31: 2883–2889

    Article  CAS  Google Scholar 

  23. Zaborowska Z, Fürste JP, Erdmann VA, Kurreck J. J Biol Chem, 2002, 277: 40617–40622

    Article  CAS  Google Scholar 

  24. Chan CWS, Khachigian LM. Internal Med J, 2009, 39: 249–251

    Article  CAS  Google Scholar 

  25. Drake JW, Holland JJ. Proc Natl Acad Sci USA, 1999, 96: 13910–13913

    Article  CAS  Google Scholar 

  26. Tian T, Wang J, Zhou X. Org Biomol Chem, 2015, 13: 2226–2238

    Article  CAS  Google Scholar 

  27. Deng H, Shen W, Ren Y, Gao Z. Biosens Bioelectron, 2014, 54: 650–655

    Article  CAS  Google Scholar 

  28. Lan T, Furuya K, Lu Y. Chem Commun, 2010, 46: 3896–3898

    Article  CAS  Google Scholar 

  29. Cheng Y, Huang Y, Lei J, Zhang L, Ju H. Anal Chem, 2014, 86: 5158–5163

    Article  CAS  Google Scholar 

  30. Saran R, Liu J. Anal Chem, 2016, 88: 4014–4020

    Article  CAS  Google Scholar 

  31. Zhou W, Saran R, Chen Q, Ding J, Liu J. ChemBioChem, 2016, 17: 159–163

    Article  CAS  Google Scholar 

  32. Torabi SF, Wu P, McGhee CE, Chen L, Hwang K, Zheng N, Cheng J, Lu Y. Proc Natl Acad Sci USA, 2015, 112: 5903–5908

    Article  CAS  Google Scholar 

  33. Liu J, Lu Y. J Am Chem Soc, 2007, 129: 9838–9839

    Article  CAS  Google Scholar 

  34. Lee JH, Wang Z, Liu J, Lu Y. J Am Chem Soc, 2008, 130: 14217–14226

    Article  CAS  Google Scholar 

  35. Huang PJJ, Vazin M, Liu J. Anal Chem, 2014, 86: 9993–9999

    Article  CAS  Google Scholar 

  36. Chen F, Wang R, Li Z, Liu B, Wang X, Sun Y, Hao D, Zhang J. Nucleic Acids Res, 2004, 32: 2336–2341

    Article  CAS  Google Scholar 

  37. Wang F, Saran R, Liu J. Bioorganic Medicinal Chem Lett, 2015, 25: 1460–1463

    Article  CAS  Google Scholar 

  38. Lermer L, Roupioz Y, Ting R, Perrin DM. J Am Chem Soc, 2002, 124: 9960–9961

    Article  CAS  Google Scholar 

  39. Chan C, Khachigian L. Curr Med Chem, 2013, 20: 3448–3455

    Article  CAS  Google Scholar 

  40. Kusunoki A, Miyano-Kurosaki N, Takaku H. Biochem Biophysical Res Commun, 2003, 301: 535–539

    Article  CAS  Google Scholar 

  41. Barua S, Ramos J, Potta T, Taylor D, Huang HC, Montanez G, Rege K. Comb Chem High Throughput Screen, 2011, 14: 908–924

    Article  CAS  Google Scholar 

  42. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l’Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Science, 2009, 326: 818–823

    Article  CAS  Google Scholar 

  43. Varkouhi AK, Scholte M, Storm G, Haisma HJ. J Control Release, 2011, 151: 220–228

    Article  CAS  Google Scholar 

  44. Huang HW, Chen FY, Lee MT. Phys Rev Lett, 2004, 92: 198304

    Article  CAS  Google Scholar 

  45. Jenssen H, Hamill P, Hancock REW. Clinical Microbiol Rev, 2006, 19: 491–511

    Article  CAS  Google Scholar 

  46. Zelphati O, Szoka Jr FC. Pharm Res, 1996, 13: 1367–1372

    Article  CAS  Google Scholar 

  47. Farhood H, Bottega R, Epand RM, Huang L. Biochim Biophys Acta-Biomembranes, 1992, 1111: 239–246

    Article  CAS  Google Scholar 

  48. Roh H, Pippin J, Drebin JA. Cancer Res, 2000, 60: 560–565

    CAS  Google Scholar 

  49. Abe T, Suzuki S, Hatta T, Takai K, Yokota T, Takaku H. Antivir Chem Chemoth, 1998, 9: 253–262

    Article  CAS  Google Scholar 

  50. Dalby B, Cates S, Harris A, Ohki EC, Tilkins ML, Price PJ, Ciccarone VC. Methods, 2004, 33: 95–103

    Article  CAS  Google Scholar 

  51. Li Y, Bhindi R, Deng ZJ, Morton SW, Hammond PT, Khachigian LM. Int J Cardiol, 2013, 168: 3659–3664

    Article  Google Scholar 

  52. Ke X, Yang Y, Hong S. Med Oncol, 2011, 28: 326–332

    Article  CAS  Google Scholar 

  53. Schwarze SR, Dowdy SF. Trends Pharmacol Sci, 2000, 21: 45–48

    Article  CAS  Google Scholar 

  54. Torchilin VP, Rammohan R, Weissig V, Levchenko TS. Proc Natl Acad Sci USA, 2001, 98: 8786–8791

    Article  CAS  Google Scholar 

  55. Torchilin VP, Levchenko TS, Rammohan R, Volodina N, Papahadjopoulos-Sternberg B, D’ Souza GGM. Proc Natl Acad Sci USA, 2003, 100: 1972–1977

    Article  CAS  Google Scholar 

  56. Turner JJ, Jones S, Fabani MM, Ivanova G, Arzumanov AA, Gait MJ. Blood Cells Mol Dis, 2007, 38: 1–7

    Article  CAS  Google Scholar 

  57. Delong R, Stephenson K, Loftus T, Fisher M, Alahari S, Nolting A, Juliano RL. J Pharm Sci, 1997, 86: 762–764

    Article  CAS  Google Scholar 

  58. Haensler J, Szoka FC. Bioconj Chem, 1993, 4: 372–379

    Article  CAS  Google Scholar 

  59. Bielinska A. Nucleic Acids Res, 1996, 24: 2176–2182

    Article  CAS  Google Scholar 

  60. Tack F, Bakker A, Maes S, Dekeyser N, Bruining M, Elissen-Roman C, Janicot M, Brewster M, Janssen HM, De Waal BFM, Fransen PM, Lou X, Meijer EW. J Drug Target, 2006, 14: 69–86

    Article  CAS  Google Scholar 

  61. Xing Z, Gao S, Duan Y, Han H, Li L, Yang Y, Li Q. Int J Nanomed, 2015, 10: 5715–5727

    CAS  Google Scholar 

  62. Meng HM, Liu H, Kuai H, Peng R, Mo L, Zhang XB. Chem Soc Rev, 2016, 45: 2583–2602

    Article  CAS  Google Scholar 

  63. Liang H, Zhang XB, Lv Y, Gong L, Wang R, Zhu X, Yang R, Tan W. Acc Chem Res, 2014, 47: 1891–1901

    Article  CAS  Google Scholar 

  64. Siepmann J, Peppas NA. Adv Drug Deliver Rev, 2012, 64: 163–174

    Article  Google Scholar 

  65. Schmidts T, Marquardt K, Schlupp P, Dobler D, Heinz F, Mäder U, Garn H, Renz H, Zeitvogel J, Werfel T, Runkel F. Int J Pharm, 2012, 431: 61–69

    Article  CAS  Google Scholar 

  66. Allen TM, Cullis PR. Science, 2004, 303: 1818–1822

    Article  CAS  Google Scholar 

  67. Mazumdar D, Liu J, Lu G, Zhou J, Lu Y. Chem Commun, 2010, 46: 1416–1418

    Article  CAS  Google Scholar 

  68. Zhou Z, Peng L, Wang X, Xiang Y, Tong A. Analyst, 2014, 139: 1178–1183

    Article  CAS  Google Scholar 

  69. Li D, Shlyahovsky B, Elbaz J, Willner I. J Am Chem Soc, 2007, 129: 5804–5805

    Article  CAS  Google Scholar 

  70. Yehl K, Joshi JP, Greene BL, Dyer RB, Nahta R, Salaita K. ACS Nano, 2012, 6: 9150–9157

    Article  CAS  Google Scholar 

  71. Somasuntharam I, Yehl K, Carroll SL, Maxwell JT, Martinez MD, Che PL, Brown ME, Salaita K, Davis ME. Biomaterials, 2016, 83: 12–22

    Article  CAS  Google Scholar 

  72. Ryoo SR, Jang H, Kim KS, Lee B, Kim KB, Kim YK, Yeo WS, Lee Y, Kim DE, Min DH. Biomaterials, 2012, 33: 2754–2761

    Article  CAS  Google Scholar 

  73. Chen Y, Yang L, Huang S, Li Z, Zhang L, He J, Xu Z, Liu L, Cao Y, Sun L. Int J Nanomed, 2013, 8: 3107–3118

    Google Scholar 

  74. Li J, Wang N, Luo Q, Wan L. Oligonucleotides, 2010, 20: 61–68

    Article  CAS  Google Scholar 

  75. Lin Tan M, Choong PF, Dass CR. Expert Opin on Drug Deliver, 2009, 6: 127–138

    Article  CAS  Google Scholar 

  76. Kurreck J. Eur J Biochem, 2003, 270: 1628–1644

    Article  CAS  Google Scholar 

  77. Schubert S. Nucleic Acids Res, 2003, 31: 5982–5992

    Article  CAS  Google Scholar 

  78. Santiago FS, Lowe HC, Kavurma MM, Chesterman CN, Baker A, Atkins DG, Khachigian LM. Nat Med, 1999, 5: 1264–1269

    Article  CAS  Google Scholar 

  79. Sun LQ, Cairns MJ, Gerlach WL, Witherington C, Wang L, King A. J Biol Chem, 1999, 274: 17236–17241

    Article  CAS  Google Scholar 

  80. Sioud M, Leirdal M. J Mol Biol, 2000, 296: 937–947

    Article  CAS  Google Scholar 

  81. Yen L, Strittmatter SM, Kalb RG. Ann Neurol, 1999, 46: 366–373

    Article  CAS  Google Scholar 

  82. Dass CR, Saravolac EG, Li Y, Sun LQ. Antisense Nucleic Acid Drug Dev, 2002, 12: 289–299

    Article  CAS  Google Scholar 

  83. Iversen PO. Blood, 2002, 99: 4147–4153

    Article  CAS  Google Scholar 

  84. Warashina M, Kuwabara T, Nakamatsu Y, Taira K. Chem Biol, 1999, 6: 237–250

    Article  CAS  Google Scholar 

  85. Wu Y, Yu L, Mc Mahon R, Rossi JJ, Forman SJ, Snyder DS. Hum Gene Ther, 1999, 10: 2847–2857

    Article  CAS  Google Scholar 

  86. Zhang L, Gasper WJ, Stass SA, Ioffe OB, Davis MA, Mixson AJ. Cancer Res, 2002, 62: 5463–5469

    CAS  Google Scholar 

  87. Robaldo L, Montserrat JM, Iribarren AM. Bioorg Med Chem Lett, 2010, 20: 4367–4370

    Article  CAS  Google Scholar 

  88. Veedu RN, Wengel J. Chem Biodivers, 2010, 7: 536–542

    Article  CAS  Google Scholar 

  89. Kaur H, Scaria V, Maiti S. Biochemistry, 2010, 49: 9449–9456

    Article  CAS  Google Scholar 

  90. Petersen M, Wengel J. Trends Biotechnol, 2003, 21: 74–81

    Article  CAS  Google Scholar 

  91. Vester B, Lundberg LB, Sørensen MD, Babu BR, Douthwaite S, Wengel J. J Am Chem Soc, 2002, 124: 13682–13683

    Article  CAS  Google Scholar 

  92. Doessing H, Vester B. Molecules, 2011, 16: 4511–4526

    Article  CAS  Google Scholar 

  93. Vester B, Wengel J. Biochemistry, 2004, 43: 13233–13241

    Article  CAS  Google Scholar 

  94. Jadhav VM, Scaria V, Maiti S. Angew Chem Int Ed, 2009, 48: 2557–2560

    Article  CAS  Google Scholar 

  95. Suryawanshi H, Lalwani MK, Ramasamy S, Rana R, Scaria V, Sivasubbu S, Maiti S. ChemBioChem, 2012, 13: 584–589

    Article  CAS  Google Scholar 

  96. Adams SR, Tsien RY. Annu Rev Physiol, 1993, 55: 755–784

    Article  CAS  Google Scholar 

  97. Young DD, Deiters A. Org Biomol Chem, 2007, 5: 999–1005

    Article  CAS  Google Scholar 

  98. Young DD, Lively MO, Deiters A. J Am Chem Soc, 2010, 132: 6183–6193

    Article  CAS  Google Scholar 

  99. Unwalla H, Banerjea AC. Biochem J, 2001, 357: 147–155

    Article  CAS  Google Scholar 

  100. Abdelgany A, Wood M, Beeson D. J Gene Med, 2007, 9: 727–738

    Article  CAS  Google Scholar 

  101. Fan H, Zhao Z, Yan G, Zhang X, Yang C, Meng H, Chen Z, Liu H, Tan W. Angew Chem, 2015, 127: 4883–4887

    Article  Google Scholar 

  102. Yuan BF, Xue Y, Luo M, Hao YH, Tan Z. Int J Biochem Cell Biol, 2007, 39: 1119–1129

    Article  CAS  Google Scholar 

  103. Deng R, Xie X, Vendrell M, Chang YT, Liu X. J Am Chem Soc, 2011, 133: 20168–20171

    Article  CAS  Google Scholar 

  104. Zhao Z, Fan H, Zhou G, Bai H, Liang H, Wang R, Zhang X, Tan W. J Am Chem Soc, 2014, 136: 11220–11223

    Article  CAS  Google Scholar 

  105. Zhang XL, Zheng C, Guo SS, Li J, Yang HH, Chen G. Anal Chem, 2014, 86: 3426–3434

    Article  CAS  Google Scholar 

  106. He ZM, Zhang PH, Li X, Zhang JR, Zhu JJ. Sci Rep, 2016, 6: 22737

    Article  CAS  Google Scholar 

  107. Muhammad F, Guo M, Qi W, Sun F, Wang A, Guo Y, Zhu G. J Am Chem Soc, 2011, 133: 8778–8781

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Key Scientific Program of China (2011CB911000), the National Basic Research Program of China (2013CB932702), the National Natural Science Foundation of China (21325520, 21327009, J1210040, 21177036), the National Instrumentation Program (2011YQ030124), and the Foundation for Innovative Research Groups of NSFC (21521063).

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Authors and Affiliations

  1. Molecular Science and Biomedicine Laboratory; State Key Laboratory of Chemo/Bio-Sensing and Chemometrics; Collaborative Innovation Center for Chemistry and Molecular Medicine; College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha, 410082, China

    Huanhuan Fan & Xiaobing Zhang

  2. Department of Chemistry, Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA

    Huanhuan Fan & Yi Lu

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  1. Huanhuan Fan
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  2. Xiaobing Zhang
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  3. Yi Lu
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Correspondence to Xiaobing Zhang or Yi Lu.

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Fan, H., Zhang, X. & Lu, Y. Recent advances in DNAzyme-based gene silencing. Sci. China Chem. 60, 591–601 (2017). https://doi.org/10.1007/s11426-016-0472-1

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