Development of 2-deoxystreptamine–nucleobase conjugates for the inhibition of oncogenic miRNA production

Tran, Thi Thu Phuong; Poulet, Sylvain; Pernak, Mélanie; Rayar, Anita Maria; Azoulay, Stéphane; Giorgio, Audrey Di; Duca, Maria

doi:10.1039/d1md00345c

Cited by 5 publications

(6 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We thus decided to design new conjugates of neomycin and histidine using different kind of linkers. First of all, we chose to conjugate histidine amino acid using the same linker we employed in the past that showed successful results in terms of binding and selectivity and containing a triazole scaffold [12d,17] . As demonstrated in our previous works, the triazole moiety can participate efficiently to RNA binding and allows for a straightforward synthesis thanks to the use of the copper‐catalyzed 1,3‐dipolar cycloaddition.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Numerous studies have demonstrated the efficacy of molecular docking in identifying small molecules binding to specific miRs. For instance, Duca et al employed molecular docking to identify a molecule binding to the miR-372 Dicer site, showcasing improved inhibitory activity compared to a known binder targeting the same site [ 99 ]. In another study, Duca et al conducted a comprehensive assessment of polyamine analogues, guided by molecular docking with the PA-1/pre-miR-372 complex.…”

Section: Identification Of Small Molecules Interacting With Mirsmentioning

confidence: 99%

“…In one of their studies, they used InfoRNA to investigate Targapre-mir-210, a bis-benzimidazole small molecule which binds to the Dicer processing site of miR-210, regulating the miR-210 hypoxic circuit in breast cancer cells [ 149 ]. They further identified 2-Dioxy streptamine conjugates and nucleobase-conjugated series that showed promising binding and inhibition of pre-miR-372, outperforming neomycin counterparts [ 99 ]. Disney et al employed diverse methodologies to identify natural products (NPs) and their miR-binding partners, using a two-dimensional combinatorial screening (2DCS) approach.…”

Section: Inhibition Of Mir Processingmentioning

confidence: 99%

“…This predictive capability sheds light on the fundamental biochemical processes governing these interactions and is not limited to proteins but extends to the identification of small molecules interacting with RNA and miRs [98]. In the realm of molecular docking, researchers can leverage this method to forecast the binding affinity of small molecules to miRs, providing a comprehensive understanding of their interactions [99]. One research application involves validating the binding of predicted small molecules with oncogenic miRs [100].…”

Section: Dockingmentioning

confidence: 99%

See 1 more Smart Citation

Targeting MicroRNAs with Small Molecules

Tadesse,

Benhamou

2024

ncRNA

View full text Add to dashboard Cite

MicroRNAs (miRs) have been implicated in numerous diseases, presenting an attractive target for the development of novel therapeutics. The various regulatory roles of miRs in cellular processes underscore the need for precise strategies. Recent advances in RNA research offer hope by enabling the identification of small molecules capable of selectively targeting specific disease-associated miRs. This understanding paves the way for developing small molecules that can modulate the activity of disease-associated miRs. Herein, we discuss the progress made in the field of drug discovery processes, transforming the landscape of miR-targeted therapeutics by small molecules. By leveraging various approaches, researchers can systematically identify compounds to modulate miR function, providing a more potent intervention either by inhibiting or degrading miRs. The implementation of these multidisciplinary approaches bears the potential to revolutionize treatments for diverse diseases, signifying a significant stride towards the targeting of miRs by precision medicine.

show abstract

“…During recent years, we developed a multimodal approach for the design of RNA ligands and, in particular, for the discovery of oncogenic miRNAs inhibitors [11e–d,12a–b] . Merging different RNA binding domains in one molecule brought both affinity and selectivity for the target and led us to the identification of compounds capable of inhibiting the biogenesis of oncogenic miRNAs in vitro and showing antiproliferative activity in cancer cells with overexpressed targeted miRNA.…”

Section: Introductionmentioning

confidence: 99%

De‐Novo Design of pre‐miR‐21 Maturation Inhibitors: Synthesis and Activity Assessment

Shcheholeva

Fernández-Remacha

Estrada‐Tejedor

et al. 2023

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Targeting RNA with small molecules is a major challenge of current medicinal chemistry, and the identification and design of original scaffolds able to selectively interact with an RNA target remains difficult. Various approaches have been developed based on classical medicinal chemistry strategies (fragment-based drug design, dynamic combinatorial chemistry, HTS or DNA-encoded libraries) as well as on advanced structural biology and biochemistry methodologies (such as X-ray, cryo-EM, NMR, or SHAPE). Here, we report the de novo design, synthesis, and biological evaluation of RNA ligands by using a straightforward and sustainable chemistry combined with molecular docking and biochemical and biophysical studies that allowed us to identify a novel pharmacophore for RNA binding. Specifically, we focused on targeting the biogenesis of microRNA-21, the well-known oncogene. This led us not only to promising inhibitors but also to a better understanding of the interactions between the small-molecule compounds and the RNA target paving the way for the rational design of efficient inhibitors with potential anticancer activity.

show abstract

Development of 2-deoxystreptamine–nucleobase conjugates for the inhibition of oncogenic miRNA production

Abstract: The discovery of new original scaffolds for selective RNA targeting is one of the main challenges of current medicinal chemistry since therapeutically relevant RNAs represent potential targets for a number...

Cited by 5 publications

References 34 publications

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

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

Targeting MicroRNAs with Small Molecules

De‐Novo Design of pre‐miR‐21 Maturation Inhibitors: Synthesis and Activity Assessment

Contact Info

Product

Resources

About