Targeting Oncogenic RNA with Sustainable and Effective Small Molecules

  • Research
Published on October 5, 2023 – Updated on October 6, 2023
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on the September 11, 2023

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In an article published in Chemistry – A European Journal in September, researchers unveiled a library of small molecules that target a well-known RNA that plays a role in promoting the development of some tumors. The five-step method for synthesizing these targeting molecules, that complies with the principles of Green Chemistry, along with their promising inhibition effect, pave the way for novel approaches in treating specific cancers.

The process of targeting RNA for the treatment of infectious, cancerous, inflammatory or rare diseases is a fast-growing therapeutic strategy. A specific area of interest in medicinal chemistry is the design of small molecules, or ligands, that can selectively bind to a selected RNA target. Most current drugs target proteins, which represent only a minuscule part of the human genome’s output. Most of its output includes a myriad of RNAs involved in many biological functions, such as transportation of genetic information, protein synthesis, gene expression regulation and cellular metabolism.

In this context, the teams of Véronique Michelet and Maria Duca at the Nice Institute of Chemistry (CNRS/Université Côte d’Azur) and IQS School of Engineering at Universitat Ramon Llull in Barcelona have developed a family of RNA ligands from a unique building block: a functionalized pyridine-type aromatic core. By modifying this core building block, they designed and synthesized a whole library of small molecules that target the production of microRNA 21 (miR-21). This microRNA is involved in many physiological and pathological processes and more specifically regulates cancer cell proliferation.


The strategy for synthesizing this ligand family is based on a key step that involves ruthenium catalysis based on an atom-economic cyclization process that is fully in line with the 12 principles of Green Chemistry. With this sustainable approach, the molecules were designed to specifically bind to the hairpin structure of pre-miR-21 and inhibit the function of the enzyme that causes miR-21 maturation.

The study reveals that the molecules selected exhibit very high affinity for pre-miR-21 and good selectivity against other nucleic acid structures. By studying their mechanism of action, the most active components of the compounds could be identified, and novel structure-activity relationships were identified. These findings, detailed in Chemistry – A European Journal, herald new sustainable strategies to target oncogenic microRNAs or their production.

 
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Press release from CNRS
Contacts

Véronique Michelet - Professeur des Universités | Institut de chimie de Nice (CNRS/Université Côte d'Azur) - veronique.michelet@univ-cotedazur.fr
Maria Duca - Chercheuse | Institut de chimie de Nice (CNRS/Université Côte d'Azur) - maria.duca@univ-cotedazur.fr

Référence

De-Novo Design of pre-miR-21 Maturation Inhibitors: Synthesis and Activity Assessment
Iryna Shcheholeva, Daniel Fernández-Remacha, Roger Estrada-Tejedor, Maria Duca et Véronique Michelet
Chem. Eur. J. 2023
https://doi.org/10.1002/chem.20230082