Charlotte Carozza
Research Mentor(s): Maurinne Bonnet
Department or Program: Biomedical and Life Sciences Summer Fellowship
Authors: Charlotte Carozza; Maurinne Bonnet, PhD; Amanda Garner, PhD
Session: Session 1: 12:00pm-12:50pm
Poster: 17
Abstract
MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that regulate gene expression by binding to target mRNAs sequences, preventing their translation into proteins or inducing their degradation. The biogenesis of miRNA involves transcription of a miRNA gene followed by cleavage of a pri-miRNA into a pre-miRNA in the nucleus, export of the pre-miRNA into the cytoplasm, and a final cleavage by the enzyme DICER, generating the active form of miRNA. miRNAs are relevant targets in medicinal chemistry, as aberrant expression of miRNAs can lead to cell proliferation, inhibition of tumor suppressors, as well as chemotherapy resistance. This project aims to search for small molecules that inhibit DICER-mediated cleavage of the pre-miRNA stem-loop structure, inducing downregulation of oncogene expression. Whereas classic medicinal chemistry would involve the time-consuming process of synthesizing, purifying, and testing hundreds of compounds, using a Direct-to-Biology approach would allow the rapid screening of a large library of molecules synthesized from commercially available scaffolds and intermediates prepared in-house. The biological activity of these molecules will be evaluated using an assay developed by our lab called catalytic enzyme-linked click chemistry assay (cat-ELCCA). The Direct-to-Biology approach will be used to screen compounds inhibiting the biogenesis of miRNA-181-a, a miRNA that is overexpressed in some types of ovarian cancer, and is responsible for chemotherapy resistance.
