Design and Implementation of Synthetic RNA Binders for the Inhibition of miR-21 Biogenesis

Abstract

Targeting RNAs using small molecules is an emerging field of medicinal chemistry and holds the promise for the discovery of efficient tools for chemical biology. MicroRNAs are particularly interesting targets since they are involved in a number of pathologies such as cancers. Indeed, overexpressed microRNAs in cancer are oncogenic and various series of inhibitors of microRNAs biogenesis have been developed in recent years. Here, we describe the structure-based design of new efficient inhibitors of microRNA-21. Starting from a previously identified hit, we performed biochemical studies and molecular docking to design a new series of optimized conjugates of neomycin aminoglycoside with artificial nucleobases and amino acids. Detailed investigation about the mode of action and the site of the interaction of the newly synthesized compounds allowed for the description of structure-activity relationships and the identification of the most important parameters for miR-21 inhibition.

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

“…A study of the site of interaction of the best binders and inhibitors showed that they indeed were bound at stem-bulge junctions and close to the site of cleavage of the Dicer enzyme. 21,24 Even with these promising results in hand, as well as with a complete structure-activity characterization of this series of conjugates, 21,22,24 the size of the obtained compounds and their high hydrophilicity represent relevant drawbacks for the physico-chemical properties of this kind of conjugates. Furthermore, neomycin is known to be a toxic drug when administered and to lack specificity when used against a particular RNA.…”

“…[16][17][18][19][20] Our group contributed to the field with the design of multimodal RNA ligands synthesized upon conjugation of various RNA binding domains bringing both affinity and selectivity for the target. [21][22][23][24] More specifically, we built conjugates, whose general structure is illustrated in Fig. 1A, between aminoglycosides (such as neomycin) that are strong but non-selective RNA ligands and natural and artificial nucleobases that are heteroaromatic compounds able to selectively recognize RNA bases and RNA base pairs, respectively.…”

Protein-based Virtual Screening Tools applied for RNA-Ligand Docking identify new Binders of the preQ1-Riboswitch

“…10 Targeting RNA with small molecules, however, is still a novel concept and only one molecule except of ribosome-targeting antibiotics is approved by the FDA. With Risdiplam, 11,12 the first approved small molecule splicing modifier is available for the treatment of spinal muscular atrophy and further splicing modifiers, micro RNA (miRNA) ligands and binders of extended trinucleotide repeats are under elucidation for many indications including cancer, 8,[13][14][15][16] neurological and genetic disorders. 2,[17][18][19][20][21][22][23] While only around 1.5% of the human genome is transcribed into proteins, the common drug-targets, about 70-90% is transcribed into RNA.…”

RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

“…The targeting of another family of noncoding RNAs, microRNAs, is also covered. A paper from the laboratory of Maria Duca from the Université Côte d’Azur describes a continuation of their efforts toward the rational design of aminoglycoside conjugates for targeting microRNA-21 (miR-21) . A collaborative contribution from the laboratories of Amanda Garner and Ashootosh Tripathi at the University of Michigan also focuses on targeting miR-21 .…”

“…A paper from the laboratory of Maria Duca from the UniversitéCote d'Azur describes a continuation of their efforts toward the rational design of aminoglycoside conjugates for targeting microRNA-21 (miR-21). 27 A collaborative contribution from the laboratories of Amanda Garner and Ashootosh Tripathi at the University of Michigan also focuses on targeting miR-21. 28 Using screening technology developed by the Garner group, 29,30 the team now discloses the discovery of natural product inhibitors of microRNA maturation.…”