Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

Giorgio, Audrey Di; Duca, Maria

doi:10.1039/c9md00195f

Cited by 56 publications

(45 citation statements)

References 103 publications

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“…Viral genomes consist of some highly conserved RNA elements that play pivotal roles in gene regulation and viral replication. Being highly structured, viral RNA motifs have emerged as potential targets for the development of small-molecule antiviral drugs ( Hermann, 2016 ; Di Giorgio and Duca, 2019 ). The HIV transactivation response (TAR) element located within the first 59 nt of the viral genome is one of the most studied RNA elements ( Stevens et al, 2006 ).…”

Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

“…The TAR RNA element, folded into a hairpin structure ( Kulinski et al, 2003 ), binds to the Tat protein to form a Tat/TAR complex that stimulates transcription and HIV-1 replication ( Le Grice, 2015 ; Connelly et al, 2016 ). Efforts have been made to interfere with Tat/TAR interactions to control HIV-1 infections, including the identification and development of TAR-targeted small molecules ( Hermann, 2016 ; Di Giorgio and Duca, 2019 ). For example, through viral screening of TAR dynamic structures against >50,000 compounds and fluorescence-based experimental assays, one study identified and validated six small molecules that were able to bind to TAR (Kd = 55 nM to 22 µM) and inhibit its interaction with Tat (Ki = 710 nM to 169 µM) ( Stelzer et al, 2011 ).…”

Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

“…Another well studied viral RNA target is the internal ribosome entry site (IRES) element located in the 5′UTR of the hepatitis C virus (HCV) viral genome ( Dibrov et al, 2014 ; Hermann, 2016 ; Di Giorgio and Duca, 2019 ). Being a highly structured RNA motif, HCV IRES functions as an RNA-based initiation factor to directly recruit host cell ribosomes with only a subset of host cell initiation factors and thus mediates cap-independent translation initiation ( Lukavsky, 2009 ).…”

Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

See 2 more Smart Citations

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

Yu¹,

Choi²,

Tu³

2020

Pharmacol Rev

214

155

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Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

Section: Rnas As Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

See 1 more Smart Citation

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

Yu¹,

Choi²,

Tu³

2020

Pharmacol Rev

214

155

View full text Add to dashboard Cite

“…Owing to their numerous cellular functions and their propensity to form secondary (and tertiary) structure, ncRNAs are attractive for their potential as targets of small therapeutic compounds 4,5 . Additionally, chemical compounds that are selective for specific structural features presented by an RNA molecule also can be versatile tools for RNA structure analysis and functional studies.…”

Section: Introductionmentioning

confidence: 99%

2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

Nikonowicz

Zhang

Chang

et al. 2020

Preprint

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RNA helices are often punctuated with non-Watson-Crick features that can be the target of chemical compounds, but progress towards identifying small molecules specific for non-canonical elements has been slow. We have used a tandem UU:GA mismatch motif (5'-UG-3':5'-AU-3') embedded within the helix of an RNA hairpin as a model to identify compounds that bind the motif specifically. The three-dimensional structure of the RNA hairpin and its interaction with a small molecule compound identified through a virtual screen are presented. The G-A of the mismatch forms a sheared pair upon which the U-U base pair stacks. The hydrogen bond configuration of the U-U pair involves the O2 of the U adjacent to the G and the O4 of the U adjacent to the A. The G-A and U-U pairs are flanked by A-U and G-C base pairs, respectively, and the mismatch exhibits greater stability than when the motif is within the context of other flanking base pairs or when the 5'-3' orientation of the G-A and U-U is swapped.Residual dipolar coupling constants were used to generate an ensemble of structures against which a virtual screen of 64,480 small molecules was performed to identify candidate compounds that the motif specifically binds. The tandem mismatch was found to be specific for one compound, 2-amino-1,3-benzothiazole-6-carboxamide, which binds with moderate affinity but extends the motif to include the flanking A-U and G-C base pairs. The finding that affinity for the UU:GA mismatch is flanking sequence dependent emphasizes the importance of motif context and potentially increases the number of small non-canonical features within RNA that can be specifically targeted by small molecules.

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“…Recent effort has focused on developing drug-like small molecules that minimize nonspecific electrostatic and stacking interactions to target RNA (Hermann 2016;Warner et al 2018;Childs-Disney and Disney 2016). These drug-like molecules are thought to primarily bind RNA through a combination of shape complementarity and hydrogen bonding (H-bonding) (Warner et al 2018;Di Giorgio and Duca 2019). Such compounds with demonstrated cellular activity have been enumerated in the R-BIND database (Morgan et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules

Kelly

Chu²,

Shi

et al. 2020

Preprint

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Identifying small molecules that selectively bind a single RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to non-specific binding of aminoglycosides and intercalators to a variety of RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities, however the ability of such compounds to discriminate against RNA stem-loops commonly found in the transcriptome has not been thoroughly assessed in all cases. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activity of three distinct RNAs, to non-specifically bind two HIV-1 stem-loop RNAs: the transactivation response element (TAR) and stem IIB in the rev response element (RREIIB). All three compounds bound to TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting substantial off-target interactions consistent with non-specific cellular activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, much like aminoglycosides, and in contrast to ligands that specifically bind riboswitches. Our results support extending the group of non-selective RNA-binders beyond aminoglycosides and intercalators to encompass drug-like compounds with capacity for non-specific hydrogen-bonding and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.

show abstract

Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

Abstract: RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified.

Cited by 56 publications

References 103 publications

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules

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