Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells

• Published in: Journal of medicinal chemistry 2022-12, Vol.65 (24), p.16338-16352
• Main Authors: Emanuelson, Cole, Ankenbruck, Nicholas, Kumbhare, Rohan, Thomas, Meryl, Connelly, Colleen, Baktash, Yasmine, Randall, Glenn, Deiters, Alexander
• Format: Article
• Language: English
• Subjects: Hepacivirus - genetics; Hepatitis C - drug therapy; Humans; Liver Neoplasms - pathology; MicroRNAs - metabolism; Virus Replication
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01141

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.