(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

Matzner, Daniel; Mayer, Günter

doi:10.1021/jm500868e

Cited by 30 publications

(18 citation statements)

References 102 publications

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“…Similar RNA switch motifs have been discovered in over 10 other flavi‐ and picornaviruses, however, none of which rise to a level of threat as a human pathogen comparable to HCV. Outside viruses, comparable deeply encapsulating ligand binding pockets in RNA are found in bacterial riboswitches which are being exploited as targets for antibiotics discovery …”

Section: Resultsmentioning

confidence: 99%

Small molecules targeting viral RNA

2016

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Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website.

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Section: Resultsmentioning

confidence: 99%

Small molecules targeting viral RNA

2016

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“…Small molecules that are structurally dissimilar to the natural ligand but which mimic its activity to selectively downregulate riboswitchcontrolled biosynthetic genes essential for growth (herein referred to as a synthetic mimic) could serve as mechanistically novel therapeutic agents [7][8][9][10][11][12] . Riboflavin (vitamin B 2 ) biosynthesis serves as one potentially attractive metabolic pathway to apply this strategy in antibacterial discovery [11][12][13][14] .…”

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confidence: 99%

“…Therefore, disrupting riboflavin biosynthesis either by synthetic mimics of FMN or enzyme inhibitors of the pathway represents a novel target for antibacterial intervention with limited predicted off-target effects. To date, little success has been achieved in identifying synthetic mimics of riboswitch ligands despite using a variety of in vitro screening strategies, including affinity-based or fragment-based screening, or structure-guided design approaches starting with natural ligands [7][8][9] . One of the best-characterized antimetabolite inhibitors to a riboswitch is roseoflavin 17 , a naturally-produced analogue of riboflavin, which targets FMN riboswitches from multiple bacterial species 11,13,18,19 .…”

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confidence: 99%

Selective small-molecule inhibition of an RNA structural element

Howe

Wang

Fischmann

et al. 2015

Nature

349

397

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Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

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“…Meanwhile, a number of antibacterial small molecule inhibitors was identified that mimic the natural ligands and influence riboswitch-controlled functions by binding selectively to the corresponding riboswitch. Some of the most potent compounds silence essential genes of bacteria, which respond to lysine, glucosamine-6-phosphate (GlcN6P), purine, cyclic-di-GMP, flavin mononucleotide (FMN) and thiamine pyrophosphate (Lünse et al, 2014; Matzner and Mayer, 2015; Schüller et al, 2016). Approaches using synthetic mimics of the natural ligands further demonstrated that riboswitches are druggable by synthetic chemistry (Howe et al, 2015).…”

Section: Regulatory and Sensory Rnas As Valuable Drug Targetsmentioning

confidence: 99%

Roles of Regulatory RNAs for Antibiotic Resistance in Bacteria and Their Potential Value as Novel Drug Targets

et al. 2017

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The emergence of antibiotic resistance mechanisms among bacterial pathogens increases the demand for novel treatment strategies. Lately, the contribution of non-coding RNAs to antibiotic resistance and their potential value as drug targets became evident. RNA attenuator elements in mRNA leader regions couple expression of resistance genes to the presence of the cognate antibiotic. Trans-encoded small RNAs (sRNAs) modulate antibiotic tolerance by base-pairing with mRNAs encoding functions important for resistance such as metabolic enzymes, drug efflux pumps, or transport proteins. Bacteria respond with extensive changes of their sRNA repertoire to antibiotics. Each antibiotic generates a unique sRNA profile possibly causing downstream effects that may help to overcome the antibiotic challenge. In consequence, regulatory RNAs including sRNAs and their protein interaction partners such as Hfq may prove useful as targets for antimicrobial chemotherapy. Indeed, several compounds have been developed that kill bacteria by mimicking ligands for riboswitches controlling essential genes, demonstrating that regulatory RNA elements are druggable targets. Drugs acting on sRNAs are considered for combined therapies to treat infections. In this review, we address how regulatory RNAs respond to and establish resistance to antibiotics in bacteria. Approaches to target RNAs involved in intrinsic antibiotic resistance or virulence for chemotherapy will be discussed.

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(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

Cited by 30 publications

References 102 publications

Small molecules targeting viral RNA

Small molecules targeting viral RNA

Selective small-molecule inhibition of an RNA structural element

Roles of Regulatory RNAs for Antibiotic Resistance in Bacteria and Their Potential Value as Novel Drug Targets

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