Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction. Issue 1 (17th January 2020)

• Record Type: Journal Article
• Authors: Martin, Céline; De Piccoli, Serena; Gaysinski, Marc; Becquart, Cécile; Azoulay, Stéphane; Di Giorgio, Audrey; Duca, Maria
• Is Part Of: ChemPlusChem. Volume 85:Issue 1(2020)
• Page Start: 207
• Page End: 216
• Publication Date: 2020-01-17
• Subjects: inhibitors -- molecular docking -- RNA -- structure-activity relationships -- therapeutics; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/cplu.201900650
• Languages: English
• ISSNs: 2192-6506

Abstract

Abstract: Targeting RNA using small molecules is now established as a very promising strategy for many therapeutic applications since coding and non‐coding RNAs bear a pivotal role both in viral and bacterial infections as well as in diseases such as cancer. Here, we focused on HIV‐1 TAR RNA as a promising target for the development of new anti‐HIV therapies but also as an ideal model to validate the discovery of original RNA ligands. First, we performed an initial screening of a library of compounds against TAR that led to the discovery of verapamil, a marketed calcium‐channel blocker, as a promising chemical structure for the development of new RNA ligands. The synthesis of a series of analogs of verapamil led to promising structure activity relationships and to the discovery of a conjugate between verapamil and an indole fragment, as an efficient and selective TAR binder able to inhibit Tat/TAR interaction with an IC50 of 18.8 μM. This work supports the potential of library screening for the discovery of original and selective RNA ligands and illustrates how existing drugs directed against protein targets still need to be studied for RNA binding as a promising strategy in the field of RNA targeting by small molecules. Abstract : New RNA binders : The screening of a library of compounds as HIV‐1 TAR RNA binders led to the discovery of verapamil, a marketed calcium‐channel blocker, as a promising scaffold for the preparation of efficient RNA binders. The chemical modification of verapamil led to the synthesis of a series of 21 new compounds, including one conjugate that shows very good affinity for TAR RNA and the ability to inhibit TAT‐Tar interaction with an IC50 value of 18.8 μM.