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Targeting RNA in mammalian systems with small molecules

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The recognition of RNA functions beyond canonical protein synthesis has challenged the central dogma of molecular biology. Indeed, RNA is now known to directly regulate many important cellular processes, including transcription, splicing, translation, and epigenetic modifications. The misregulation of these processes in disease has led to an appreciation of RNA as a therapeutic target. This potential was first recognized in bacteria and viruses, but discoveries of new RNA classes following the sequencing of the human genome have invigorated exploration of its disease‐related functions in mammals. As stable structure formation is evolving as a hallmark of mammalian RNAs, the prospect of utilizing small molecules to specifically probe the function of RNA structural domains and their interactions is gaining increased recognition. To date, researchers have discovered bioactive small molecules that modulate phenotypes by binding to expanded repeats, microRNAs, G‐quadruplex structures, and RNA splice sites in neurological disorders, cancers, and other diseases. The lessons learned from achieving these successes both call for additional studies and encourage exploration of the plethora of mammalian RNAs whose precise mechanisms of action remain to be elucidated. Efforts toward understanding fundamental principles of small molecule–RNA recognition combined with advances in methodology development should pave the way toward targeting emerging RNA classes such as long noncoding RNAs. Together, these endeavors can unlock the full potential of small molecule‐based probing of RNA‐regulated processes and enable us to discover new biology and underexplored avenues for therapeutic intervention in human disease. This article is categorized under: RNA Methods > RNA Analyses In Vitro and In Silico RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions RNA in Disease and Development > RNA in Disease
Example cellular processes and interactions regulated by RNA structures in noncoding regions. Left: In the nucleus, structured regions in pre‐mRNAs can regulate alternative splicing. Structured noncoding RNAs can recruit transcription factors to genomic loci, interacting with both proteins and DNA. Formation of tRNA‐like structures can promote cleavage from a longer transcript and export of the RNA fragment into the cytoplasm. Right: In both the nucleus and the cytoplasm, sequence‐based changes such as single nucleotide polymorphisms (SNPs) or modifications such as m6A can alter RNA structure, which can in turn affect RNA function or protein binding. Noncoding RNAs can sequester proteins in specific cytoplasmic regions. RNA structures in UTRs can limit translation rates by impeding the initiation step. Despite the simple hairpin structures shown for clarity, cellular RNAs are known to adopt various complex structures. Abbreviations: m6A = 6‐methyladenosine; SNP = single nucleotide polymorphism; UTR = untranslated region. (Reprinted with permission from Bevilacqua, Ritchey, Su, and Assmann (). Copyright 2016 Annual Reviews, Inc.)
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Small molecule‐induced regulation of the SMN2 splicing mechanism. (a) The splicing mechanism of SMN1 (healthy protein) and SMN2 (disease protein) in which exon 7 is included due to a SNP. (b) Small molecules shown to induce exon 7 stabilization in SMN2 gene. Abbreviations: ESE = exonic splicing enhancer; hnRNP G = heterogeneous nuclear ribonucleoprotein G; SMN = survival motor neuron; SNP = single nucleotide polymorphism; snRNP = small nuclear ribonucleoprotein; ss = splice site
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Structure, function, and small molecule binders of G‐quadruplexes. (a) Nucleotide composition and base‐pairing interactions in an RNA G‐quadruplex and stacking of multiple G‐quadruplexes. (Reprinted with permission from Agarwala, Pandey, and Maiti () Copyright 2015 Royal Society of Chemistry.) (b) Regulation of cap‐dependent and independent translation by G‐quadruplexes. (Reprinted with permission from Bugaut and Balasubramanian () Copyright 2012 Oxford University Press.) (c) Examples of small molecule stabilizers of G‐quadruplexes in 5′‐UTRs. Abbreviations: Bcl‐X = B‐cell lymphoma‐extra; IRES = internal ribosomal entry site; KRAS = Kirsten rat sarcoma viral oncogene homolog; M+ = monovalent metal cation; m7G = 7‐methylguanylate; NRAS = neuroblastoma RAS viral oncogene homolog; ss = splice site
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Traditional and emerging screens to identify small molecule miRNA inhibitors. (a) A standard luciferase‐based reporter system used to identify small molecule miRNA inhibitors. Increase in luciferase signal indicative of translation is assumed to be caused by small molecule binding to miRNA or one if its precursors, thereby reducing binding of the mature miRNA to its target sequence. (Reprinted with permission from Wen et al. () Copyright 2015 Elsevier Ltd.) (b) A click‐chemistry‐based assay to identify small molecule inhibitors of Dicer‐mediated processing. Abbreviations: RISC = RNA‐induced silencing complex. (Reprinted with permission from Lorenz and Garner (). Copyright 2016 Royal Society of Chemistry)
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Small molecule‐based targeting of the miRNA biogenesis pathway. (a) Mechanism of action of miRNA‐mediated gene silencing. (b) Example small molecule inhibitors of miRNA biogenesis. Abbreviations: pre‐miRNA = precursor miRNA; pri‐miRNA = primary miRNA; RISC = RNA‐induced silencing complex
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The RNA processing effect induced by expanded repeats and representative structures of single expansions in select diseases. (a) In normal repeat RNA, splicing proteins, and transcription factors are available for proper processing to mature mRNA isoforms. When repeats are expanded in disease, proteins needed for efficient splicing are sequestered, leading to excess of mis‐spliced mRNA isoforms. (Reprinted with permission from Todd and Paulson () Copyright 2009 John Wiley & Sons, Inc.). (b) Secondary structures of repeat RNA and their associated diseases. Abbreviations: DMPK = DM1 protein kinase; FMR1 = fragile X mental retardation 1; HTT = Huntington gene; N = nucleotide; ZNF9 = zinc finger protein 9. (Reprinted with permission from Blaszczyk, Rypniewski, and Kiliszek (). Copyright 2017 John Wiley & Sons, Inc.)
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Small molecule‐based targeting of r(CUG)exp repeats in DM1. (a) CTG expansion in the DMPK locus results in the transcription of r(CUG)exp repeats that then sequester MBNL proteins, leading to some of the characteristic phenotypes in DM1. Abbreviations: DMPK = DM1 protein kinase; MBNL = muscle‐blind protein 1. (b) Representative small molecule inhibitors of steps in DM1 repeat pathogenesis
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RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
RNA Methods > RNA Analyses In Vitro and In Silico

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