Methods to identify and optimize small molecules interacting with RNA (SMIRNAs)

Ursu, Andrei; Vézina‐Dawod, Simon; Disney, Matthew D.

doi:10.1016/j.drudis.2019.06.019

Cited by 24 publications

(27 citation statements)

References 97 publications

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“…[104] Prompted by prior studies that indicated that triple-stranded RNAs prefer an A-form conformation, [105][106][107] Sekine and coworkers found that s2U bases in triplex forming oligos (TFOs) could also bind AU sites in dsRNA to form triplexes; [108] they subsequently exploited the enhanced stacking of the thione substitution with 4-thiopseudoisocytidine (s 4 ΨiC) bases in TFOs to target GC base pairs in dsRNAs. [109,110] The Chen lab later demonstrated that both s2U and s 4 ΨiC could also target AU and GC pairs in dsRNA when the thio bases are presented on a PNA backbone, driven only by gains in base stacking and hydrogen-bonding in the absence of a sugar backbone. [15,111,112]…”

Section: Native Cytidine and Uridine Derivatives That Stabilize Trimentioning

confidence: 99%

“…[2][3][4][5][6][7] Thoroughly reviewed work from the Dervan lab [8] on minor groove targeting polypyrrole amides [9,10] will not be discussed in depth here, though these systems have been studied in a wide range of applications, including DNase and restriction enzyme inhibition, [11,12] site-specific cleavage, [13] replication/ transcription termination, [14] and dicer inhibition. [15] Similarly, due to space limitations, we will not deeply discuss small molecule reagents, [16][17][18] library approaches to binding nucleic acid, [2,4,7] and more recently reviewed triplex motifs. [19] We will focus discussion instead on unnatural bases that mimic native interfaces to target noncoding motifs using nucleic acid and peptide nucleic acid backbones [20] through steric, electrostatic, and hydrogen bond complementation considerations.…”

Section: Introductionmentioning

confidence: 99%

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Unnatural bases for recognition of noncoding nucleic acid interfaces

et al. 2020

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The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible with the DNA/RNA coding interface have the potential to expand the genetic code and co‐opt the machinery of biology to access new macromolecular function; accordingly, this body of research is core to synthetic biology. While much of the literature on artificial bases focuses on code expansion, there is a significant and growing effort on docking synthetic heterocycles to noncoding nucleic acid interfaces; this approach seeks to illuminate major processes of nucleic acids, including regulation of transcription, translation, transport, and transcript lifetimes. These major avenues of research at the coding and noncoding interfaces have in common fundamental principles in molecular recognition. Herein, we provide an overview of foundational literature in biophysics of base recognition and unnatural bases in coding to provide context for the developing area of targeting noncoding nucleic acid interfaces with synthetic bases, with a focus on systems developed through iterative design and biophysical study.

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Section: Native Cytidine and Uridine Derivatives That Stabilize Trimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unnatural bases for recognition of noncoding nucleic acid interfaces

et al. 2020

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“…Similarly, Benner and others [1] have shown that functional and orthogonal synthetic base pairs may be prepared by shuffling Watson‐Crick interfaces, yielding new pairs that are biophysically similar to native nucleic acids [9–11] . Recently, high throughput screening (HTS) of small molecule libraries have been applied to noncanonical RNA folds, [12–16] in analogy to the approach for protein targets. Though selected designed systems [1,17–24] and RNA HTS [13,25–27] have yielded many important findings, general principles for targeting non‐duplex secondary structures remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, high throughput screening (HTS) of small molecule libraries have been applied to noncanonical RNA folds, [12–16] in analogy to the approach for protein targets. Though selected designed systems [1,17–24] and RNA HTS [13,25–27] have yielded many important findings, general principles for targeting non‐duplex secondary structures remain elusive. We hypothesized that a semi‐rational approach akin to fragment‐based strategies [28,29] that includes both design and screening could be useful to gain insight into targeting of individual and tandem noncanonical pairs (NCPs) within internal bulges.…”

Section: Introductionmentioning

confidence: 99%

Screening of Minimalist Noncanonical Sites in Duplex DNA and RNA Reveals Context and Motif‐Selective Binding by Fluorogenic Base Probes

Liang

Miao

Mao

et al. 2021

Chemistry A European J

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We hypothesize that programmable hybridization to noncanonical nucleic acid motifs may be achieved by macromolecular display of binders to individual noncanonical pairs (NCPs). As each recognition element may individually have weak binding to an NCP, we developed a semi‐rational approach to detect low affinity interactions between selected nitrogenous bases and noncanonical sites in duplex DNA and RNA. A set of fluorogenic probes was synthesized by coupling abiotic (triazines, pyrimidines) and native RNA bases to thiazole orange (TO) dye. This probe library was screened against duplex nucleic acid substrates bearing single abasic, single NCP, and tandem NCP sites. Probe engagement with NCP sites was reported by 100–1000× fluorescence enhancement over background. Binding is strongly context‐dependent, reflective of both molecular recognition and stability: less stable motifs are more likely to bind a synthetic probe. Further, DNA and RNA substrates exhibit entirely different abasic and single NCP binding profiles. While probe binding in the abasic and single NCP screens was monotonous, much richer binding profiles were observed with the screen of tandem NCP sites in RNA, in part due to increased steric accessibility. In addition to known binding interactions between the triazine melamine (M) and T/U sites, the NCP screens identified new targeting elements for pyrimidine‐rich motifs in single NCPs and 2×2 internal bulges. We anticipate that semi‐rational approaches of this type will lead to programmable noncanonical hybridization strategies at the macromolecular level.

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“…An AbsorbArray is a small molecule microarray-based approach that allows for unmodified compounds to noncovalently adhere onto surfaces of an agarose-coated microarray to bind to RNA-motif libraries in a massively parallel format [98]. Using this platform, Hafeez et al have designed a small molecule (TGP-377) that specifically and potently enhances vascular endothelial growth factor a (VEGFA) expression by targeting miR-377 and VEGFA mRNA [99].…”

Section: Identifying New Drugs Using Microarraymentioning

confidence: 99%

Microarrays and NGS for Drug Discovery

Pop¹,

Zănoagă²,

Chiroi³

et al. 2021

Drug Design - Novel Advances in the Omics Field and Applications

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Novel technologies and state of the art platforms developed and launched over the last two decades such as microarrays, next-generation sequencing, and droplet PCR have provided the medical field many opportunities to generate and analyze big data from the human genome, particularly of genomes altered by different diseases like cancer, cardiovascular, diabetes and obesity. This knowledge further serves for either new drug discovery or drug repositioning. Designing drugs for specific mutations and genotypes will dramatically modify a patient’s response to treatment. Among other altered mechanisms, drug resistance is of concern, particularly when there is no response to cancer therapy. Once these new platforms for omics data are in place, available information will be used to pursue precision medicine and to establish new therapeutic guidelines. Target identification for new drugs is necessary, and it is of great benefit for critical cases where no alternatives are available. While mutational status is of highest importance as some mutations can be pathogenic, screening of known compounds in different preclinical models offer new and quick strategies to find alternative frameworks for treating more diseases with limited therapeutic options.

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Methods to identify and optimize small molecules interacting with RNA (SMIRNAs)

Cited by 24 publications

References 97 publications

Unnatural bases for recognition of noncoding nucleic acid interfaces

Unnatural bases for recognition of noncoding nucleic acid interfaces

Screening of Minimalist Noncanonical Sites in Duplex DNA and RNA Reveals Context and Motif‐Selective Binding by Fluorogenic Base Probes

Microarrays and NGS for Drug Discovery

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