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Philipps-Universität Marburg
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Abstract
Optochemical tools serve as potent instruments for the modulation of RNA-based processes. This thesis
introduces innovative development in the optochemical control of RNA splicing and translation regulation,
utilizing photoswitchable small molecules and peptide nucleic acids (PNAs).
In one part of this thesis (Chapter 3.1 and 3.3), an approach involving visible light-responsive peptide nucleic
acids (PNAs) for the manipulation of oligonucleotide hybridization was introduced. The synthesis of these
PNAs involved the conjugation with photoswitches (ortho-tetrafluoroazobenzene (oF4Azo), hemithioindigo,
and spiropyran). The subsequent synthesis and detailed photochemical characterization were expounded
upon. The studies revealed the promising attributes of oF4Azo-PNA conjugates, including rapid and reversible
isomerization, remarkable thermal stability, high isomer conversion, and sensitivity to visible-light irradiation.
Through melting experiments and strand-displacement assays, the investigation explored light-controlled
oligonucleotide hybridization, showing modest yet discernible differences induced by light. Combining
oF4Azo-PNAs with cell-penetrating peptides (CPPs) yielded light-responsive antisense agents for use in living
cells. With distinct goals of redirecting mRNA splicing and mimicking microRNA to inhibit cancer cell growth,
the PNA-CPPs demonstrated favorable outcomes. However, it was observed that the degree of light
controllability was limited. The subsequent development of cyclic PNAs was introduced, alongside various
synthetic approaches. Studies indicated that the ring size influenced oligonucleotide hybridization.
Another part of this thesis (Chapter 3.2) delved into the development of reversible mRNA splicing regulation
through photoswitchable small molecules. The synthesis and comprehensive photochemical analysis of
synthesized molecules were meticulously detailed. The best compound, Me-oF2Azo-BOX, exhibited rapid and
reversible photoisomerization, good thermal stability, and significant differences in enhancing exon inclusion
in splicing between photostationary states. This studies underscored its capability to achieve real-time
conditional control at both mRNA and protein levels, which could be reversibly regulated by light. Molecular
mechanisms of action were further elucidated.
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Dates
Created: 2023Issued: 2024-07-22Updated: 2024-07-31
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
eng
Data types
DoctoralThesis
DDC-Numbers
540
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Zhang, Lei: Optochemical Regulation of mRNA-Based Processes. : Philipps-Universität Marburg 2024-07-22. DOI: https://doi.org/10.17192/z2023.0679.