Structure–Activity Relationships of Anti-microRNA Oligonucleotides Containing Cationic Guanidine-Modified Nucleic Acids

Abstract

Anti-microRNA oligonucleotides (AMOs) are valuable tools for the treatment of diseases caused by the dysregulation of microRNA expression. However, the correlation between chemical modifications in AMO sequences and the microRNA-inhibitory activity has not been fully elucidated. In this study, we synthesized a series of AMOs containing cationic guanidine-bridged nucleic acids (GuNA) and evaluated their activities using a dual luciferase assay. We also optimized the site of GuNA substitution and found an effective design for the inhibition of microRNA-21, which was partially different from that of conventional nucleic acid derivatives. This study showed that GuNA-substituted AMOs are effective in inhibiting the function of microRNA.

Parallel synthesis of oligonucleotides containing N-acyl amino-LNA and their therapeutic effects as anti-microRNAs

“…Our previous work on GuNA-modified AMO suggests that the interaction of the 2′-guanidino group of GuNA-modified AMO with its neighboring amino acids of Argonaute 2 in miRISC may enhance the inhibitory activity of AMO. 64 Further, in this study, the activity of AMOs changed depending on the structure of the substituent at the 2′ position of ALNA, indicating that an interaction between the 2′-amino substituent and miRISC may be involved.…”

“…62,63 Recently, we reported that AMOs composed of guanidinebridged nucleic acid (GuNA), have excellent anti-microRNA activity, and slight changes in the modification process can greatly enhance AMO activity. 64 Interactions between AMOs and proteins may contribute to the change in activity and warrant further investigation. We focused on the development of AMOs with 2′-N-acyl derivatives of ALNA to generate new interactions between proteins and AMOs by introducing a carbonyl group at the 2′-position of ALNA.…”

The Expanded Central Dogma: Genome Resynthesis, Orthogonal Biosystems, Synthetic Genetics

“…The repeating negative charges on the nucleic acid backbone inhibit passive transport across cell membranes. Recent endeavors to address this challenge target the phosphodiester backbone directly and introduce uncharged linkages, as in alkyl phosphonate nucleic acids (phNA) and phosphoryl guanidine oligonucleotides (PGOs) ( 49 ) or even positively charged guanidine-bridged nucleic acids (GuNA) ( 102 , 104 ). While these approaches are elegant solutions to a physicochemical problem, they are still limited by larger problems like antisense-binding affinity to RNA targets, cost-efficient availability of starting materials, and ease of synthesis.…”

miRNA-Based Technologies in Cancer Therapy

“…The inhibition of oncogenic miRNAs has been achieved by antisense oligonucleotides (anti-microRNA oligonucleotides-AMOs), also called antagomirs, miRNA sponges, and miRNA-Masking Antisense Oligonucleotides [120][121][122][123]. Table 1 and Figure 1 show the main miRNA therapeutic strategies.…”