Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells.
Cole EmanuelsonNicholas AnkenbruckRohan KumbhareMeryl ThomasColleen ConnellyYasmine BaktashGlenn RandallAlexander DeitersPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- hepatitis c virus
- small molecule
- cell proliferation
- long non coding rna
- high throughput
- transcription factor
- long noncoding rna
- poor prognosis
- human immunodeficiency virus
- nuclear factor
- induced apoptosis
- gene expression
- dna methylation
- toll like receptor
- cell cycle arrest
- genome wide
- immune response
- signaling pathway
- hiv infected
- crispr cas
- antiretroviral therapy
- inflammatory response
- cell death
- heat shock
- climate change
- drug induced
- liver injury