Thomas, Meryl
(2015)
Syntheses and applications of small molecule inhibitors of miRNAs miR-21 and miR-122.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
MicroRNAs (miRNAs) are regulatory RNA molecules of 22 nucleotides that (in part) control up to 60% of all genes in humans. They act by binding to the 3' untranslated regions of target messenger RNAs, leading either to translational repression or mRNA degradation. In addition to being involved in the regulation of several fundamental cellular processes, the misregulation of miRNAs has been linked to a wide range of diseases including cancer. Particularly, miR-21 is significantly upregulated in nearly all types of human cancers, and its overexpression is often associated with poor prognosis. The downregulation of miR-122 is found in more than 70% of hepatocellular carcinoma cases and miR-122 is a required factor for the replication of the HCV virus. The modulation of miRNA function is commonly achieved using oligonucleotide agents. However, compared to oligonucleotides, small molecules have several advantages, such as fast activity, systemic delivery, and excellent cell permeability. Taking advantage of luciferase-based reporters, two separate high-throughput screens of >300,000 compounds each, were conducted to discover new small molecule inhibitors of miR-21 or miR-122. Several hit compounds were re-synthesized, their ability to inhibit miR-21 was validated, and the most promising compounds were investigated by SAR studies, which revealed two additional, structurally diverse classes of miR-21 inhibitors. Similarly, extensive SAR studies of previously discovered miR-122 inhibitors were performed in order to better understand the molecular requirements for the miR-122 inhibitory activity. The hit compounds identified in the HTS were analyzed through secondary assays that led to the identification of two new promising miR-122 inhibitors. Furthermore, the knowledge gained during the SAR studies was further used to synthesize several small molecule miR-21/miR-122 inhibitors as probes to explore their mechanisms of action. MicroRNAs represent promising, novel drug targets, and small molecule miRNA inhibitors provide tools to study the molecular mechanisms of miRNA biogenesis and have the potential to be new therapeutic agents for the treatment of cancers and viral infections.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
27 September 2015 |
| Date Type: |
Publication |
| Defense Date: |
24 July 2015 |
| Approval Date: |
27 September 2015 |
| Submission Date: |
4 August 2015 |
| Access Restriction: |
3 year -- Restrict access to University of Pittsburgh for a period of 3 years. |
| Number of Pages: |
397 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
microRNAs, miR-21, miR-122, HCV, HCC, small molecules, inhibitors |
| Date Deposited: |
27 Sep 2016 05:00 |
| Last Modified: |
27 Sep 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/25898 |
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