Targeting RNA structures with small molecules

Childs‐Disney, Jessica L.; Yang, Xueyi; Gibaut, Quentin M. R.; Tong, Yuquan; Batey, Robert T.; Disney, Matthew D.

doi:10.1038/s41573-022-00521-4

Cited by 243 publications

(253 citation statements)

References 310 publications

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“…The discovery, development and implementation of additional applications of riboswitches are ongoing and gaining momentum [ 181 ]. Bacterial gene-regulatory RNAs in general and riboswitches in particular appear as ideal molecular tools and antibacterial drug targets.…”

Section: Discussionmentioning

confidence: 99%

A Riboswitch-Driven Era of New Antibacterials

et al. 2022

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Riboswitches are structured non-coding RNAs found in the 5′ UTR of important genes for bacterial metabolism, virulence and survival. Upon the binding of specific ligands that can vary from simple ions to complex molecules such as nucleotides and tRNAs, riboswitches change their local and global mRNA conformations to affect downstream transcription or translation. Due to their dynamic nature and central regulatory role in bacterial metabolism, riboswitches have been exploited as novel RNA-based targets for the development of new generation antibacterials that can overcome drug-resistance problems. During recent years, several important riboswitch structures from many bacterial representatives, including several prominent human pathogens, have shown that riboswitches are ideal RNA targets for new compounds that can interfere with their structure and function, exhibiting much reduced resistance over time. Most interestingly, mainstream antibiotics that target the ribosome have been shown to effectively modulate the regulatory behavior and capacity of several riboswitches, both in vivo and in vitro, emphasizing the need for more in-depth studies and biological evaluation of new antibiotics. Herein, we summarize the currently known compounds that target several main riboswitches and discuss the role of mainstream antibiotics as modulators of T-box riboswitches, in the dawn of an era of novel inhibitors that target important bacterial regulatory RNAs.

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Section: Discussionmentioning

confidence: 99%

A Riboswitch-Driven Era of New Antibacterials

et al. 2022

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“…Guanidines and amidines are often regarded as excessively basic, although p K a is actually very sensitive to substitution for these functional groups and can readily be controlled over a wide range. , The p K a values shown in parentheses for guanidine substituted with acetyl (8.2), pyridaz-3-yl (8.3), oxazol-2-yl (5.8 for 4-methyl analog) and methylsulfonyl (1.8 for aminosulfonyl) suggest that these compounds may be of interest for screening as fragments. A number of compounds that incorporate the guanidine substructure are of interest as ligands for RNAs implicated in infectious disease …”

Section: Hydrogen-bond Donors and Target Recognitionmentioning

confidence: 99%

“…A number of compounds that incorporate the guanidine substructure are of interest as ligands for RNAs implicated in infectious disease. 18 Close contacts between aromatic CH and HBAs have been observed in many crystal structures, 116 but the importance of these as determinants of binding affinity is rather less clear. Although HB acidity measurements do not appear to have been reported for aromatic CH HBDs, it would be reasonable to assume that the HB acidity of benzene is comparable to that of 1heptyne (α 2 H = 0.13; Table 1).…”

Section: ■ Aqueous Solubilitymentioning

confidence: 99%

“…Hydrogen bonding stabilizes three-dimensional structures of drug targets, such as proteins and RNA, and is also an important determinant of binding affinity of drugs for their targets and antitargets. However, the importance of individual ligand-target HBs cannot be inferred simply from inspection of the structure of a target-ligand complex since the contribution of an intermolecular contact to affinity is generally not an experimental observable .…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen-Bond Donors in Drug Design

Kenny¹

2022

J. Med. Chem.

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Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.

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“…For example, the affinity of RNA-binding compounds can be affected by ionic strength as well as other factors. Perhaps, a more informative analysis would evaluate QED and bioactivity, which could be complicated by differences in the RNA-targeted small molecules’ modes of action and if the small molecules inhibit the RNA target substoichiometrically, for example, degraders …”

Section: Discussionmentioning

confidence: 99%

Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells

et al. 2022

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RNA is challenging to target with bioactive small molecules, particularly those of low molecular weight that bind with sufficient affinity and specificity. In this report, we developed a platform to address this challenge, affording a novel bioactive interaction. An RNA-focused small-molecule fragment collection (n = 2500) was constructed by analyzing features in all publicly reported compounds that bind RNA, the largest collection of RNA-focused fragments to date. The RNA-binding landscape for each fragment was studied by using a library-versus-library selection with an RNA library displaying a discrete structural element, probing over 12.8 million interactions, the greatest number of interactions between fragments and biomolecules probed experimentally. Mining of this dataset across the human transcriptome defined a drug-like fragment that potently and specifically targeted the microRNA-372 hairpin precursor, inhibiting its processing into the mature, functional microRNA and alleviating invasive and proliferative oncogenic phenotypes in gastric cancer cells. Importantly, this fragment has favorable properties, including an affinity for the RNA target of 300 ± 130 nM, a molecular weight of 273 Da, and quantitative estimate of drug-likeness (QED) score of 0.8. (For comparison, the mean QED of oral medicines is 0.6 ± 0.2). Thus, these studies demonstrate that a low-molecular weight, fragment-like compound can specifically and potently modulate RNA targets.

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Targeting RNA structures with small molecules

Cited by 243 publications

References 310 publications

A Riboswitch-Driven Era of New Antibacterials

A Riboswitch-Driven Era of New Antibacterials

Hydrogen-Bond Donors in Drug Design

Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells

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