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Article Dans Une Revue ACS Chemical Biology Année : 2022

Small-Molecule 3D Ligand for RNA Recognition: Tuning Selectivity through Scaffold Hopping

Résumé

Targeting RNAs with small molecules is considered the next frontier for drug discovery. In this context, the develop-ment of compounds capable of binding RNA structural motifs of low complexity with high affinity and selectivity would greatly expand the number of targets of potential therapeutic value. In this study, we demonstrate that tuning the three-dimensional shape of promiscuous nucleic acid binders is a valuable strategy for the design of new selective RNA ligands. Indeed, starting from a known cyanine, the simple replacement of a phenyl ring with a [2.2]paracyclophane moiety led to a new compound able to discriminate between nucleic acids showing different structural characteristics with a marked affinity and selectivity for an octahairpin loop RNA sequence. This shape modification also affected the in cellulo behavior of the cyanine. These results suggest that scaffold hopping is a valua-ble strategy to improve the selectivity of RNA/small-molecule interactions and highlight the need to explore new chemical space for the design of selective RNA ligands.
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Dates et versions

hal-04035021 , version 1 (17-03-2023)

Identifiants

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Simon Felder, Corinne Sagné, Erica Benedetti, Laurent Micouin. Small-Molecule 3D Ligand for RNA Recognition: Tuning Selectivity through Scaffold Hopping. ACS Chemical Biology, 2022, 17 (11), pp.3069-3076. ⟨10.1021/acschembio.2c00171⟩. ⟨hal-04035021⟩
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