The Bioactivity of D-/L-Isonucleoside- and 2′-Deoxyinosine-Incorporated Aptamer AS1411s Including DNA Replication/MicroRNA Expression

Xinmeng Fan, Lidan Sun, Kunfeng Li, Xiantao Yang, Baobin Cai, Yanfen Zhang, Yuejie Zhu, Yuan Ma, Zhu Guan, Yun Wu, Lihe Zhang, Zhenjun Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

25 Citations (Scopus)

Abstract

In this study, chemical modification of 2′-deoxyinosine (2′-dI) and D-/L-isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the different phases of the tumor cell cycle, induced S-phase arrest, promoted the inhibition of DNA replication, and suppressed the unwound function of a large T antigen as powerful as AS1411. The microarray analysis and TaqMan PCR results showed that FCL-II can upregulate the expression of four breast-cancer-related, lowly expressed miRNAs and downregulate the expression of three breast-cancer-related, highly expressed miRNAs (>2.5-fold). FCL-II resulted in enhanced treatment effects greater than AS1411 in animal experiments (p < 0.01). The computational results further proved that FCL-II exhibits more structural advantages than AS1411 for binding to the target protein nucleolin, indicating its great potential in antitumor therapy.

Original languageEnglish
Pages (from-to)218-229
Number of pages12
JournalMolecular Therapy Nucleic Acids
Volume9
Early online date30 Sept 2017
DOIs
Publication statusPublished - 15 Dec 2017

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

User-Defined Keywords

  • 2'-deoxyinosine
  • AS1411
  • biological regulation
  • isonucleoside
  • tumor suppressor

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