RNA as a small molecule druggable target

Rizvi, Noreen F.; Smith, G. F.

doi:10.1016/j.bmcl.2017.10.052

Cited by 67 publications

(58 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By analogy, it is possible to induce a transcriptional gene network whose output is therapeutic for a given clinical indication by targeting the druggable master regulators of the transcriptional network. Such targets may include large protein complexes involved in chromatin remodeling (Crabtree et al, 2018); transiently expressed transcription factors once thought to be undruggable (Crunkhorn, 2018;Sievers et al, 2018); functional regulatory RNAs, such as long noncoding RNA (lncRNA), microRNA, piRNA, and mRNA (Rizvi and Smith, 2017); or through alteration of a network gene or enhancer using direct genome editing delivered through gene therapy or viral vectors (Sheridan, 2017).…”

Section: A Master Regulators Of Transcriptional Network As Druggablmentioning

confidence: 99%

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

et al. 2019

View full text Add to dashboard Cite

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in cis and trans. Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder,

show abstract

Section: A Master Regulators Of Transcriptional Network As Druggablmentioning

confidence: 99%

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

et al. 2019

View full text Add to dashboard Cite

show abstract

“…A lot of previously reported review articles have described the same subject as that of our review article but in more detail …”

Section: Interaction Of Small Molecules With Long Nonprotein Coding Rmentioning

confidence: 99%

Interaction of small molecules with polynucleotide repeats and frameshift site RNA

Nemr

Yousif

Barciszewski

2019

Archiv der Pharmazie

View full text Add to dashboard Cite

This mini‐review describes the interaction between small molecules and RNA, in addition to its application either in treating RNA‐associated diseases or detecting target molecules. In the case of RNA‐associated disease treatment, the designed small molecules interact with RNA sites, forming adducts and providing successful therapeutic strategies over oligonucleotides. On the other hand, synthetically designed RNA moieties (aptamers) interact with target molecules like toxins, drugs, hormones; these interactions are useful in the detection, quantification or separation of these target moieties.

show abstract

“…Natural small molecule metabolites bind specifically and tightly to riboswitches in 5'-untranslated regions (5'UTR) of messenger RNAs (mRNA), altering conformation and regulating transcription elongation or translation initiation. Thus, analogs of a metabolite can have a lethal effect on expression of a single essential gene (15)(16)(17)(18). Resistance to antibiotics that target a single riboswitch can occur frequently, and strains resistant to an inhibitor of the riboflavin riboswitch have readily emerged (19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria

Väre

Schneider

Kim

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Bacterial infections and the rise of antibiotic resistance, especially multidrug resistance, have generated a clear need for discovery of novel therapeutics. We demonstrated that a small molecule drug PKZ18 targets the T-box mechanism and inhibits bacterial growth. The T-box is a structurally conserved riboswitch-like gene regulator in the 5′-untranslated region of numerous essential genes of Gram-positive bacteria. T-boxes are stabilized by cognate, unacylated tRNA ligands, allowing the formation of an anti-terminator hairpin in the mRNA that enables transcription of the gene. In the absence of an unacylated cognate tRNA, transcription is halted due to the formation of a thermodynamically more stable terminator hairpin. PKZ18 targets the site of the codon/anticodon interaction of the conserved Stem I and reduces T-box controlled gene expression. Here we show that novel analogs of PKZ18 have improved minimum inhibitory concentrations, bactericidal effects against methicillin resistant Staphylococcus aureus (MRSA), and increased efficacy in nutrient limiting conditions. The analogs have reduced cytotoxicity against eukaryotic cells compared to PKZ18. The PKZ18 analogs acted synergistically with aminoglycosides to significantly enhance the efficacy of the analogs and aminoglycosides, further increasing their therapeutic windows. RNA sequencing showed that the analog PKZ18-22 affects expression of 8 of 12 T-box controlled genes in a statistically significant manner, but not other 5′UTR regulated genes in MRSA. Very low levels of resistance further support the existence of multiple T-box targets for PKZ18 analogs in the cell. Together the multiple targets, low resistance, and synergy make PKZ18 analogs promising drugs for development and future clinical applications.

show abstract

RNA as a small molecule druggable target

Cited by 67 publications

References 52 publications

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

Interaction of small molecules with polynucleotide repeats and frameshift site RNA

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria

Contact Info

Product

Resources

About