Date of Award

Spring 2025

Language

English

Embargo Period

4-22-2025

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College/School/Department

Department of Chemistry

Program

Chemistry

First Advisor

Ting Wang

Committee Members

Ting Wang, Jia Sheng

Keywords

Small molecule, Photoswitch, RNA therapy, Myotonic Dystrophy

Subject Categories

Nucleic Acids, Nucleotides, and Nucleosides | Polycyclic Compounds

Abstract

RNA plays a critical role in many biological functions, such as normal cellular functions or disease-related processes. Regulating biological processes through RNA-based therapeutics can be employed by the reversible photoregulation of oligonucleotides. Azobenzene, a light-responsive compound that changes conformation when exposed to ultraviolet (UV) or visible light, is attached to cytidine phosphoramidite to be incorporated in a series of RNA oligonucleotides. The reversibility of the nucleoside and oligonucleotide is verified through UV melting point experiments. The modified oligonucleotide can change conformation upon light irradiation to stop reverse transcription (RT) in the presence of many different reverse transcriptase enzymes. This technique can be used to optically control RNA structures and functions for gene therapy by limiting off-target effects. A redshifted azobenzene could be explored for safer biological applications using longer wavelengths of light.

Myotonic Dystrophy Type 1 (DM1) is a genetic disorder caused by expanded CTG repeats in the DMPK gene, leading to the sequestration of Muscleblind-like (MBNL) protein. The sequestration of this protein disrupts RNA splicing. Small molecules are emerging as promising drug candidates specifically polycyclic compounds in recently approved FDA pharmaceuticals. In this study, the use of modified polycyclic compounds (MPCs) is being explored as a splicing modulator. The MPC targets the toxic CUG repeat-expanded RNA, thereby rescuing MBNL proteins and restoring correct RNA processing. The synthetic route, purification, and characterization in our symmetrical benzoxazole MPC is being studied for its possible solubility advantages in aqueous solutions.

License

This work is licensed under the University at Albany Standard Author Agreement.

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