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α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells.
ACS Appl Mater Interfaces 2018; 10(11):9736-9743AA

Abstract

Because of the chemical simplicity of α-l-threose nucleic acid (TNA) and its ability to exchange genetic information between itself and RNA, it has attracted significant interest as the RNA ancestor. We herein explore the biological properties and evaluate the potency of sequence-designed TNA polymers to suppress the gene expression in living environments. We found that sequence-specific TNA macromolecules exhibit strong affinity and specificity toward the complementary RNA targets, are highly biocompatible and nontoxic in a living cell system, and readily enter a number of cell lines without using transfecting agents. Particularly, TNA exhibited much stronger enzymatic resistance toward fetal bovine serum or human serum as compared to traditional antisense oligonucleotides, which means that the intrinsic structure of TNA is thoroughly resistant to biological degradation. Importantly, the efficacy of the TNA molecule with green fluorescent protein (GFP) target sequence (anti-GFP TNAs) as antisense agents was first demonstrated in living cells in which these polymers revealed high antisense activity in terms of the degree of inhibition of GFP gene expression. The GFP gene inhibition studies in HeLa and HEK293 cells characterize sequence-controlled TNA as a functional biomaterial and a valuable alternative to traditional antisense oligonucleotides such as peptide nucleic acids, phosphorodiamidate morpholino oligomers, and locked nucleic acids for a wide range of applications in drug discovery and life science research. Additionally, we also first reported the cost-efficient approach to synthesize the four TNA phosphoramidite monomers using 2-cyanoethyl N, N, N', N'-tetraisopropylphosphoramidite as a key reagent. Furthermore, by increasing the frequency of the deblocking and coupling reactions together with extending their reaction time in each synthesis cycle, sequence-controlled TNAs can be easily synthesized in a quantitative yield and high purity.

Authors+Show Affiliations

Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China. Key Laboratory of Biochip Technology, Biotech and Health Care , Shenzhen Research Institute of City University of Hong Kong , Shenzhen 518057 , China.Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China. Key Laboratory of Biochip Technology, Biotech and Health Care , Shenzhen Research Institute of City University of Hong Kong , Shenzhen 518057 , China.Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China. Key Laboratory of Biochip Technology, Biotech and Health Care , Shenzhen Research Institute of City University of Hong Kong , Shenzhen 518057 , China.Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China.Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China.Department of Chemistry , City University of Hong Kong , Tat Chee Avenue , Kowloon Tong , Hong Kong SAR , China. Key Laboratory of Biochip Technology, Biotech and Health Care , Shenzhen Research Institute of City University of Hong Kong , Shenzhen 518057 , China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29473733

Citation

Liu, Ling Sum, et al. "Α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells." ACS Applied Materials & Interfaces, vol. 10, no. 11, 2018, pp. 9736-9743.
Liu LS, Leung HM, Tam DY, et al. Α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells. ACS Appl Mater Interfaces. 2018;10(11):9736-9743.
Liu, L. S., Leung, H. M., Tam, D. Y., Lo, T. W., Wong, S. W., & Lo, P. K. (2018). Α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells. ACS Applied Materials & Interfaces, 10(11), pp. 9736-9743. doi:10.1021/acsami.8b01180.
Liu LS, et al. Α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells. ACS Appl Mater Interfaces. 2018 Mar 21;10(11):9736-9743. PubMed PMID: 29473733.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - α-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells. AU - Liu,Ling Sum, AU - Leung,Hoi Man, AU - Tam,Dick Yan, AU - Lo,Tsz Wan, AU - Wong,Sze Wing, AU - Lo,Pik Kwan, Y1 - 2018/03/08/ PY - 2018/2/24/pubmed PY - 2018/2/24/medline PY - 2018/2/24/entrez KW - antisense KW - gene inhibition KW - green fluorescent protein expression KW - therapeutics KW - α-l-threose nucleic acid SP - 9736 EP - 9743 JF - ACS applied materials & interfaces JO - ACS Appl Mater Interfaces VL - 10 IS - 11 N2 - Because of the chemical simplicity of α-l-threose nucleic acid (TNA) and its ability to exchange genetic information between itself and RNA, it has attracted significant interest as the RNA ancestor. We herein explore the biological properties and evaluate the potency of sequence-designed TNA polymers to suppress the gene expression in living environments. We found that sequence-specific TNA macromolecules exhibit strong affinity and specificity toward the complementary RNA targets, are highly biocompatible and nontoxic in a living cell system, and readily enter a number of cell lines without using transfecting agents. Particularly, TNA exhibited much stronger enzymatic resistance toward fetal bovine serum or human serum as compared to traditional antisense oligonucleotides, which means that the intrinsic structure of TNA is thoroughly resistant to biological degradation. Importantly, the efficacy of the TNA molecule with green fluorescent protein (GFP) target sequence (anti-GFP TNAs) as antisense agents was first demonstrated in living cells in which these polymers revealed high antisense activity in terms of the degree of inhibition of GFP gene expression. The GFP gene inhibition studies in HeLa and HEK293 cells characterize sequence-controlled TNA as a functional biomaterial and a valuable alternative to traditional antisense oligonucleotides such as peptide nucleic acids, phosphorodiamidate morpholino oligomers, and locked nucleic acids for a wide range of applications in drug discovery and life science research. Additionally, we also first reported the cost-efficient approach to synthesize the four TNA phosphoramidite monomers using 2-cyanoethyl N, N, N', N'-tetraisopropylphosphoramidite as a key reagent. Furthermore, by increasing the frequency of the deblocking and coupling reactions together with extending their reaction time in each synthesis cycle, sequence-controlled TNAs can be easily synthesized in a quantitative yield and high purity. SN - 1944-8252 UR - https://www.unboundmedicine.com/medline/citation/29473733/α_l_Threose_Nucleic_Acids_as_Biocompatible_Antisense_Oligonucleotides_for_Suppressing_Gene_Expression_in_Living_Cells_ L2 - https://dx.doi.org/10.1021/acsami.8b01180 DB - PRIME DP - Unbound Medicine ER -