Chemistry ETDs

Publication Date

Summer 7-11-2018

Abstract

MiRNAs are key cellular regulators and their dysregulation is associated with many human diseases. The development of miRNA inhibitors has significant implications for the therapy of diseases associated with aberrant miRNA expression. It also provides chemical tools for studying miRNA function. This dissertation focuses on the development of small-molecule based miRNA inhibitors targeting miRNA biogenesis.

The dissertation consists of four chapters. In Chapter 1, the biogenesis of miRNA was first introduced, followed by the explanation of miRNA function in health and disease. Then the approaches used for regulating miRNA were reviewed. Finally, the difficulties with miRNA regulation were summarized.

One of the key reactions in miRNA biogenesis is the processing of pre-miRNA by Dicer enzyme. In Chapter 2, we developed a general strategy for inhibiting miRNA biogenesis with bifunctional small molecules. By linking a pre-miRNA binder and a weak Dicer inhibiting unit, we obtained bifunctional conjugates that are able to block the Dicer processing of pre-miRNA and inhibit miRNA production. This approach is expected to be applicable in generating more inhibitors for other miRNAs.

MiRNAs are usually produced locally in a spatiotemporally controlled manner to regulate gene expression. Thus, developing chemical tools for manipulating miRNA with spatiotemporal preciseness is critical for studying miRNA. In Chapter 3, we expanded the application of the strategy described in Chapter 2 in generating light controllable miRNA inhibitors. By conjugating the two functional units with a photocleavable linker, we made a new bifunctional miRNA inhibitor. Taking advantage of the photocleavage property of the linker, the bifunctional inhibitor can be fragmented into separate non-inhibiting units and therefore be deactivated by light. We expect that this strategy could be applied to generate chemical biological tools that allow light-mediated spatiotemporal control of miRNA maturation and contribute to the study of miRNA function.

In Chapter 4, we investigated the potential of targeting miRNA with macrocyclic peptidomimetics. By screening a combinatory library of peptidomimetics against pre-miR-155, we identified a pre-miR-155 binder that is able to block the Dicer processing, thereby reduce oncogenic miR-155 level and induce apoptosis in cancer cells. This compound could be used as a lead for generating more potent miR-155 inhibitors. The results of this investigation also demonstrate that macrocyclic peptidomimetics could serve as new small molecule scaffolds for RNA targeting.

Language

English

Keywords

miRNA, inhibior, aminoglycosides, macrocyclopeptidomimetic, bifunctional molecule, photocleavage

Document Type

Dissertation

Degree Name

Chemistry and Chemical Biology

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Fu-Sen Liang

Second Committee Member

Lina Cui

Third Committee Member

Rebecca S. Hartley

Fourth Committee Member

Wei Wang

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