Small molecule chemical probes of microRNA function

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have been explored as diagnostic markers and therapeutic targets. Although it is challenging to target RNA with small molecules in general, there have been successful campaigns that have identified small molecule modulators of miRNA function by targeting various pathways. For example, small molecules that modulate transcription and target nuclease processing sites in miRNA precursors have been identified. Herein, we describe challenges in developing chemical probes that target miRNAs and highlight aspects of miRNA cellular biology elucidated by using small molecule chemical probes. We expect that this area will expand dramatically in the near future as strides are made to understand small molecule recognition of RNA from a fundamental perspective.

Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting

“…While it is still very difficult to rationally design RNA binding agents that would be specific for a particular RNA sequence and structure, [8][9][10] there is an urgent need for new hits that could represent the starting material for the synthesis of selective RNA binding agents. In this work, we decided to investigate how rRNA-targeting antibiotics could be applied to the inhibition of oncogenic miRNAs production through the inhibition of the last step of miRNAs biogenesis, that is, the cleavage of stem-loop structured pre-miRNAs by the enzyme Dicer leading to mature oncogenic miRNA.…”

“…7 To date, only few small-molecule modifiers of miRNA pathways have been reported. 5,[8][9][10] Most of them were discovered after the screening of libraries containing thousands of compounds [11][12][13] or after the evaluation of focused libraries containing fewer compounds known to act as general RNA binders. [14][15][16] Disney and coworkers also described a very efficient lead identification strategy for RNA motif/small molecule interactions, named Inforna, and they applied it to human pre-miRNAs.…”

Covalent and non-covalent binding of metal complexes to RNA

“…Some successful examples include the design of cyclic peptides able to target HIV-1 (human immunodeficiency virus) RNA [36] and of modularly assembled compounds targeting expanded nucleotide repeats that cause neuromuscular diseases [37]. Also, small molecules able to modulate miRNA functions were identified [33,38]. Surprisingly, the RNA binding abilities of small metal complexes, which can bind to RNA both covalently and non-covalently, have been much less explored [3,39,40].…”

“…Thus, a constant effort is being made to identify the main features ruling the interaction between small molecules and RNA, in order to design compounds displaying selective binding affinity for a specific RNA target. It seems that high-throughput screening followed by synthetic optimization may lead to the development of molecules with high RNA affinity and specificity [31][32][33][34][35]. Some successful examples include the design of cyclic peptides able to target HIV-1 (human immunodeficiency virus) RNA [36] and of modularly assembled compounds targeting expanded nucleotide repeats that cause neuromuscular diseases [37].…”

“…The latter is so rich in non-canonical elements that their targeting represents a challenging but powerful way to interfere with RNA function. Along this line, a few small molecules have been developed that are able to target RNAs [31][32][33][34]. For example, different classes of antibiotics, including, e.g., aminoglycosides and tetracyclines, are known to exert their effect by targeting bacterial RNA [31].…”