Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells.
J Med Chem
; 65(24): 16338-16352, 2022 12 22.
Article
em En
| MEDLINE
| ID: mdl-36449366
ABSTRACT
MicroRNAs (miRNAs) are noncoding RNA molecules of 22-24 nucleotides that are estimated to regulate thousands of genes in humans, and their dysregulation has been implicated in many diseases. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and has been linked to the development of hepatocellular carcinoma and hepatitis C virus (HCV) infection. Its role in these diseases renders miR-122 a potential target for small-molecule therapeutics. Here, we report the discovery of a new sulfonamide class of small-molecule miR-122 inhibitors from a high-throughput screen using a luciferase-based reporter assay. Structure-activity relationship (SAR) studies and secondary assays led to the development of potent and selective miR-122 inhibitors. Preliminary mechanism-of-action studies suggest a role in the promoter-specific transcriptional inhibition of miR-122 expression through direct binding to the liver-enriched transcription factor hepatocyte nuclear factor 4α. Importantly, the developed inhibitors significantly reduce HCV replication in human liver cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hepatite C
/
MicroRNAs
/
Neoplasias Hepáticas
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos