Biology Reference
In-Depth Information
Chapter 12
Identifi cation of Inhibitors of MicroRNA Function
from Small Molecule Screens
Colleen M. Connelly and Alexander Deiters
Abstract
Aberrant expression of microRNAs (miRNAs) has been linked to many human diseases including cancer,
immune disorders, heart disease, and viral infections. Thus, small molecule inhibitors of miRNAs have
potential as new therapeutic agents, as probes for the elucidation of detailed mechanisms of miRNA func-
tion, and as tools for the discovery of new targets for the treatment of human diseases. In order to identify
small molecule inhibitors of specifi c miRNAs, functional assays have been developed and applied to the
screening of small molecule libraries. Here, we report the application of a luciferase-based reporter assay
of miRNA miR-122 function to the discovery of small molecule miR-122 inhibitors.
Key words
MicroRNA, Cell-based assay, Luciferase, High-throughput screen, Small molecule
inhibitor
1
Introduction
The aberrant expression of microRNAs (miRNAs) has been linked
to many human diseases including cancer, immune disorders, heart
disease, and viral infections [
1
-
5
]. Given that miRNAs can play
critical roles in cancer and other diseases, it is important to under-
stand their biogenesis, regulation, and function. Small molecule
inhibitors of miRNAs could serve as the necessary tools for eluci-
dating the regulation and function of specifi c miRNAs and could
be lead structures for the development of new therapeutic agents
[
6
]. Several regulatory tools to control the function of individual
miRNAs have previously been developed and applied to functional
studies, including antisense oligonucleotides or antagomirs [
7
,
8
],
miRNA sponges, and miRNA decoys [
9
]. However, these nucleic
acid-based molecules face diffi culties as tools to study miRNA bio-
genesis and as potential therapeutics. A few of the major drawbacks
include the high cost for in vivo studies, susceptibility to enzymatic
degradation, poor cellular uptake and systemic distribution, low oral
bioavailability, and the potential for immune responses [
10
,
11
].
