Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction

Martin, Cosette; Piccoli, Serena De; Gaysinski, Marc; Becquart, Cécile; Azoulay, Stéphane; Giorgio, Audrey Di; Duca, Maria

doi:10.1002/cplu.201900650

Cited by 7 publications

(3 citation statements)

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“…Our laboratory has since synthesized ∼60 derivatives, some of which have high specificity for select viral RNAs ( 88 , 89 , 90 ). Other scaffolds investigated for RNA binding through scaffold optimization have included benzimidazoles ( 91 ), aminoglycoside–benzimidazole conjugates ( 92 , 93 , 94 , 95 ), 2-aminobenzoxazoles ( 96 ), thienopyridines ( 97 ), diarylpyridines ( 98 ), diaryltriazines ( 99 ), oxazolidinones ( 100 ), 3,5-diamino-piperidines ( 101 , 102 ), diphenylfurans ( 14 , 67 , 103 , 104 , 105 ), verapamil ( 106 ), methylquinolinium derivatives ( 107 ), aminoquinolones ( 108 ), and triptycene-based molecules designed for DNA and RNA junctions ( 109 ) ( Fig. 3 ).…”

Section: Framework 2: Potential Existence Of An Rna-biased Chemical Smentioning

confidence: 99%

Frameworks for targeting RNA with small molecules

Juru

Hargrove

2021

Journal of Biological Chemistry

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Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins, RNA molecules play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. Through these interactions, RNAs mediate cellular processes such as the regulation of gene transcription and the enhancement or inhibition of protein activity. As a result, the misregulation of RNA molecules is often associated with disease phenotypes, and RNA molecules have been increasingly recognized as potential targets for drug development efforts, which in the past had focused primarily on proteins. Although both small molecule–based and oligonucleotide-based therapies have been pursued in efforts to target RNA, small-molecule modalities are often favored owing to several advantages including greater oral bioavailability. In this review, we discuss three general frameworks (sets of premises and hypotheses) that, in our view, have so far dominated the discovery of small-molecule ligands for RNA. We highlight the unique merits of each framework as well as the pitfalls associated with exclusive focus of ligand discovery efforts within only one framework. Finally, we propose that RNA ligand discovery can benefit from using progress made within these three frameworks to move toward a paradigm that formulates RNA-targeting questions at the level of RNA structural subclasses.

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Section: Framework 2: Potential Existence Of An Rna-biased Chemical Smentioning

confidence: 99%

Frameworks for targeting RNA with small molecules

Juru

Hargrove

2021

Journal of Biological Chemistry

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“…The effective inhibition of Tat/TAR interaction with a potent ligand may suppress viral replication. A series of verapamil derivatives, reported by Duca and co‐workers, [67] was demonstrated as the TAR‐selective ligand. One of these analogues ( 2 h ) bearing an indole substituent group was found efficiently inhibiting Tat/TAR interaction in vitro (IC 50 =18.8 μM).…”

Section: Rna Structure‐targeting Small Molecule Ligands For Drug Disc...mentioning

confidence: 99%

RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

Chan,

Wang,

Zheng

et al. 2023

ChemMedChem

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RNA structures, including those formed from coding and noncoding RNAs, alternative to protein‐based drug targets, could be a promising target of small molecules for drug discovery against various human diseases, particularly in anticancer, antibacterial and antivirus development. The normal cellular activity of cells is critically dependent on the function of various RNA molecules generated from DNA transcription. Moreover, many studies support that mRNA‐targeting small molecules may regulate the synthesis of disease‐related proteins via the non‐covalent mRNA‐ligand interactions that do not involve gene modification. RNA‐ligand interaction is thus an attractive approach to address the challenge of “undruggable” proteins in drug discovery because the intracellular activity of these proteins is hard to be suppressed with small molecule ligands. We selectively surveyed a specific area of RNA structure‐selective small molecule ligands in fluorescence live cell imaging and drug discovery because the area was currently underexplored. This state‐of‐the‐art review thus mainly focuses on the research published within the past three years and aims to provide the most recent information on this research area; hopefully, it could be complementary to the previously reported reviews and give new insights into the future development on RNA‐specific small molecule ligands for live cell imaging and drug discovery.

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“…[13] Concomitantly, we also pursued screening studies to search for new RNA binders with successful results both in the targeting of oncogenic microRNAs and viral RNAs. [14] In this work, we decided to take advantage of the RNA binding properties of neomycin to explore its RNA cleavage ability upon conjugation with imidazole-containing compounds (Figure 1A). More specifically, we studied the effect of histidine conjugation to neomycin on the TAR RNA fragment that represents an ideal model as well as an interesting biological target.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Neomycin‐Imidazole Conjugates for RNA Cleavage

et al. 2022

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Targeting RNA with synthetic small molecules attracted much interest during recent years as a particularly promising therapeutic approach in a large number of pathologies spanning from genetic disorders, cancers as well as bacterial and viral infections. In this work, we took advantage of a known RNA binder, neomycin, to prepare neomycin-imidazole conjugates mimicking the active site of ribonuclease enzymes able to induce a site-specific cleavage of HIV-1 TAR RNA in physiological conditions. These new conjugates were prepared using a straightforward synthetic methodology and were studied for their ability to bind the target, inhibit Tat/TAR interaction and induce selective cleavage using fluorescencebased assays and molecular docking. We found compounds with nanomolar affinity, promising cleavage activity and the ability to inhibit Tat/TAR interaction with submicromolar IC 50 s.

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Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction

Cited by 7 publications

References 50 publications

Frameworks for targeting RNA with small molecules

Frameworks for targeting RNA with small molecules

RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

Design, Synthesis, and Evaluation of Neomycin‐Imidazole Conjugates for RNA Cleavage

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