Chemical modification and design of anti-miRNA oligonucleotides

Abstract

Antisense techniques have been employed for over 30 years to suppress expression of target RNAs. Recently, microRNAs (miRNAs) have emerged as a new class of small, non-coding, regulatory RNA molecules that widely impact gene regulation, differentiation and disease states in both plants and animals. Antisense techniques that employ synthetic oligonucleotides have been used to study miRNA function and some of these compounds may have potential as novel drug candidates to intervene in diseases where miRNAs contribute to the underlying pathophysiology. Anti-miRNA oligonucleotides (AMOs) appear to work primarily through a steric blocking mechanism of action; these compounds are synthetic reverse complements that tightly bind and inactivate the miRNA. A variety of chemical modifications can be used to improve the performance and potency of AMOs. In general, modifications that confer nuclease stability and increase binding affinity improve AMO performance. Chemical modifications and/or certain structural features of the AMO may also facilitate invasion into the miRNA-induced silencing complex. In particular, it is essential that the AMO binds with high affinity to the miRNA 'seed region', which spans bases 2-8 from the 5¢-end of the miRNA.

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

“…Furthermore, four miRNAs (miR18a*, miR1403p, miR629*, and let7b) were higher, and three miRNAs (miR328, miR422a, and miR8555p) were lower in the mucosa of active CD patients compared with inactive CD patients. [135,136] . A study by Janssen et al [137] demonstrated that miravirsen, an LNAantimiR122, is designed to target and inhibit miR122, and this can reduce viral RNA levels in patients with chronic hepatitis C virus infection.…”

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

“…Restoring the level of deficient miRNA can be achieved by using miRNA mimics, representing synthetically prepared miRNAs [16,17]; or viral constructs, encoding for miRNAs [18,19]. Suppression of miRNA activity can be achieved using small-molecule inhibitors, acting at the transcriptional level [20]; via miRNA sponges, representing transcripts that contain multiple tandem-binding sites adsorbing deleterious miRNAs [21,22]; by miR-mask oligonucleotides or target protectors, that are fully complementary to predicted miRNA binding sites in the 3′-UTR of the target mRNA [23][24][25]; and using antisense oligonucleotides, complementary to the target miRNA and inducing either its degradation or steric blockage [26,27].…”

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

“…The first miRNA inhibitors were antisense oligonucleotides [15] that bind to mature miRNA sequences within the cell. To enhance their stability and increase their affinity for a specific miRNA, chemical modifications such as 2ʹO methyl ribose sugars, locked ribose rings (locked nucleic acid, ‘LNA’, nucleotides) and phosphorothioate backbone linkages were employed [16–18].…”