Small-molecule screening of ribonuclease L binders for RNA degradation.
Biomed Pharmacother
; 154: 113589, 2022 Oct.
Article
em En
| MEDLINE
| ID: mdl-36029542
ABSTRACT
Small molecules targeting the ubiquitous latent ribonuclease (RNase L), which has limited sequence specificity toward single-stranded RNA substrates, hold great potential to be developed as broad-spectrum antiviral drugs by modulating the RNase L-mediated innate immune responses. The recent development of proximity-inducing bifunctional molecules, as described in the strategy of ribonuclease targeting chimeras, demonstrated that small-molecule RNase L activators can function as the essential RNase L-recruiting component to design bifunctional molecules for targeted RNA degradation. However, only a single screening study on small-molecule RNase L activators with poor potency has been reported to date. Herein, we established a FRET assay and conducted a screening of 240,000 small molecules to identify new RNase L activators with improved potency. The extremely low hit rate of less than 0.03% demonstrated the challenging nature of RNase L activation by small molecules available from current screening collections. A few hit compounds induced enhanced thermal stability of RNase L upon binding, although validation assays did not lead to the identification of compounds with significantly improved RNase L activating potency. The sulfonamide compound 17 induced a thermal shift of ~ 0.9 °C upon binding to RNase L, induced significant apoptosis in cancer cells, and showed single-digit micromolar inhibitory activity against cancer cell proliferation. This study paves the way for future structural optimization for the development of small-molecule RNase L binders.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
RNA
/
Endorribonucleases
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
Biomed Pharmacother
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha