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

Yu, Aiming; Choi, Young Hee; Tu, Mei Juan

doi:10.1124/pr.120.019554

Cited by 273 publications

(228 citation statements)

References 488 publications

(773 reference statements)

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“…The mechanism of action of tetracycline is based on the binding of the molecule at the A site of the 30S subunit of the ribosome, a connection that involves the 16S rRNA [39]. The presence of tetracycline blocks tRNA binding and consequently the inhibition of protein synthesis [40]. tet(O) and tet(M) are paralogs of EF-G, a translation GTPase, and are able to remove tetracycline from the ribosome dependent on the GTP hydrolysis [41].…”

Section: Discussionmentioning

confidence: 99%

Occurrence of tet(O/M/O) Mosaic Gene in Tetracycline-Resistant Campylobacter

et al. 2020

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Campylobacter is one of the most important microorganisms responsible for foodborne diseases in the EU. In this study, we investigated resistance to tetracycline in 139 Campylobacter jejuni and Campylobacter coli samples isolated from human clinical cases. From these, 110 were resistant to tetracycline, with MIC (minimal inhibitory concentration) varying in a range of 1 to >512 μg/mL, and 109 (78.4%) carried tet(O), a gene that confers resistance to tetracycline through the expression of a protein that confers protection to the ribosome. Amongst the tetracycline-resistant isolates, one C. jejuni (HCC30) was the only tet(O)-negative sample, presenting an MIC of 256 μg/mL. Instead, the mosaic gene tet(O/M/O) was found in HCC30 and, as far as we know, this is the first description of this chimeric gene originating from homologous recombination between tet(O) and tet(M). The previously described mosaic gene tet(O/32/O), also found in Campylobacter, presents a chimeric structure very similar to that of tet(O/M/O), affecting domains II and III of encoded proteins distantly related to the elongation factor G (EF-G). The tet(O/M/O) mosaic gene has been found in nucleotide databases in several genomes of Campylobacter isolated from different origins, indicating its frequent acquisition, even though it can be undetected through screening by PCR with specific tet(O) primers. In this work, we address the improvement of classical PCR to efficiently diagnose the most prevalent tetracycline resistance determinants in Campylobacter, including tet(O/M/O), which should be taken into account in the optimization of campylobacteriosis treatments.

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Section: Discussionmentioning

confidence: 99%

Occurrence of tet(O/M/O) Mosaic Gene in Tetracycline-Resistant Campylobacter

et al. 2020

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“…Small molecules bind non-coding RNAs and structure/function base assays can be developed to select these molecules [ 63 , 64 ]. A new class of antibacterial reagent is a novel hybrid small molecule but has yet to be shown for long-term resistance or active against biofilms [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

et al. 2021

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Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains.

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“…In light of these concerns, our view is that a major progress in the field could be the identification of drug-like small molecules able to target specifically the ncRNAs of interest, as they may guarantee a better pharmacokinetic profile and cost-efficiency as compared to nucleic acid-based oligomers ( Figure 1 b). In the context of miRNAs, some small molecules have been reported to inhibit miRNA biogenesis by blocking the processing sites for Drosha or Dicer on primary or precursor miRNAs, respectively (reviewed in [ 105 ] and in [ 106 ]). This is made possible by the fact that secondary motifs, namely hairpin structures, present in such transcripts are available for ligand binding.…”

Section: Targeting Ncrnas To Interrupt Tumor-caf Interplaymentioning

confidence: 99%

“…This is made possible by the fact that secondary motifs, namely hairpin structures, present in such transcripts are available for ligand binding. As for miRNAs reported to play a role in tumor-stroma interplay, precursors of miR-21 and miR-210 showed to be efficiently bound by the small molecules mitoxantrone and a bisbenzimide analog called targarpremir-miR-210, respectively, which resulted in impaired processing and reduced mature miRNA availability [ 105 , 106 ]. To our knowledge, no small molecules have been described to target mature miRNAs directly.…”

Section: Targeting Ncrnas To Interrupt Tumor-caf Interplaymentioning

confidence: 99%

Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

Tassinari

Gandellini

2021

Cancers

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Cancer development and progression are not solely cell-autonomous and genetically driven processes. Dynamic interaction of cancer cells with the surrounding microenvironment, intended as the chemical/physical conditions as well as the mixture of non-neoplastic cells of the tumor niche, drive epigenetic changes that are pivotal for the acquisition of malignant traits. Cancer-associated fibroblasts (CAF), namely fibroblasts that, corrupted by cancer cells, acquire a myofibroblast-like reactive phenotype, are able to sustain tumor features by the secretion of soluble paracrine signals and the delivery extracellular vesicles. In such diabolic liaison, a major role has been ascribed to noncoding RNAs. Defined as RNAs that are functional though not being translated into proteins, noncoding RNAs predominantly act as regulators of gene expression at both the transcriptional and post-transcriptional levels. In this review, we summarize the current knowledge of microRNAs and long noncoding RNAs that act intracellularly in either CAFs or cancer cells to sustain tumor-stroma interplay. We also report on the major role of extracellular noncoding RNAs that are bidirectionally transferred between either cell type. Upon presenting a comprehensive view of the existing literature, we provide our critical opinion regarding the possible clinical utility of tumor-stroma related noncoding RNAs as therapeutic target/tools or prognostic/predictive biomarkers.

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

Cited by 273 publications

References 488 publications

Occurrence of tet(O/M/O) Mosaic Gene in Tetracycline-Resistant Campylobacter

Occurrence of tet(O/M/O) Mosaic Gene in Tetracycline-Resistant Campylobacter

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

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