Small Molecule Modifiers of MicroRNA miR-122 Function for the Treatment of Hepatitis C Virus Infection and Hepatocellular Carcinoma

MicroRNAs are a recently discovered new class of important endogenous regulators of gene function. Aberrant regulation of microRNAs has been linked to various human diseases, most importantly cancer. Small molecule intervention of microRNA misregulation has the potential to provide new therapeutic a...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2010-06, Vol.132 (23), p.7976-7981
Main Authors: Young, Douglas D, Connelly, Colleen M, Grohmann, Christoph, Deiters, Alexander
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Base Sequence
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Enoxacin - pharmacology
HeLa Cells
Hepatitis C - drug therapy
Hepatitis C - genetics
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - genetics
Liver Neoplasms - pathology
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
MicroRNAs - metabolism
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - pharmacology
Virus Replication - drug effects
Virus Replication - genetics
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Summary:MicroRNAs are a recently discovered new class of important endogenous regulators of gene function. Aberrant regulation of microRNAs has been linked to various human diseases, most importantly cancer. Small molecule intervention of microRNA misregulation has the potential to provide new therapeutic approaches to such diseases. Here, we report the first small molecule inhibitors and activators of the liver-specific microRNA miR-122. This microRNA is the most abundant microRNA in the liver and is involved in hepatocellular carcinoma development and hepatitis C virus (HCV) infection. Our small molecule inhibitors reduce viral replication in liver cells and represent a new approach to the treatment of HCV infections. Moreover, small molecule activation of miR-122 in liver cancer cells selectively induced apoptosis through caspase activation, thus having implications in cancer chemotherapy. In addition to providing a new approach for the development of therapeutics, small molecule modifiers of miR-122 function are unique tools for exploring miR-122 biogenesis.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja910275u