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DC Element | Wert | Sprache |
---|---|---|
dc.contributor.advisor | Waldmann, Herbert | - |
dc.contributor.author | Chang, Jen-Yao | - |
dc.date.accessioned | 2024-02-07T07:34:45Z | - |
dc.date.available | 2024-02-07T07:34:45Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://hdl.handle.net/2003/42315 | - |
dc.identifier.uri | http://dx.doi.org/10.17877/DE290R-24152 | - |
dc.description.abstract | WD repeat domain 5 (WDR5) is a scaffold protein involved in protein-protein or RNA-protein complexes, and most of these complexes play an important role in various epigenetic modulation processes. In particular, some of the long non-coding RNAs (lncRNAs) rely on the formation of the lncRNA-WDR5 complex to exert their epigenetic modulation, such as the upregulation of the lncRNA itself. If an oncogenic lncRNA relies on this pathway to maintain its expression level, it is possible to inhibit its positive feedback loop and thus reduce the expression of the oncogenic lncRNA. Therefore, this thesis focuses on investigating the potential of targeting lncRNA-WDR5 interactions, followed by evaluating the downregulation of lncRNA in cellulo. Targeting lncRNA-WDR5 interactions could be achieved by designing an inhibitor that targets the same binding pocket on WDR5. Several lncRNA are reported to recognize WDR5-binding motif (WBM) site, as a result, a study of structure-activity relationship of peptide-based inhibitors derivatize from protein-WDR5 interactions to target WBM site are performed. Further optimizations are performed by tailor-design macrocycle structure to facilitate peptides adopt the binding conformation and indeed the binding affinity is improved. The ability of macrocycle to disrupt lncRNA-protein interaction is verified by competitive in vitro RNA immunoprecipitation (iv-RIP). Cellular experiments are performed to determine whether targeting lncRNA-WDR5 interactions leads to downregulation of the lncRNA itself. Several strategies show their ability to enhance cell uptake of macrocycles. Finally, two molecules show that targeting lncRNA-WDR5 complexes can lead to reduction of the lncRNA itself and that different lncRNA have different sensitivity to the treatment. | en |
dc.language.iso | en | de |
dc.subject | RNA-protein interactions | en |
dc.subject | HOTTIP | en |
dc.subject | WDR5 | en |
dc.subject.ddc | 570 | - |
dc.subject.ddc | 540 | - |
dc.title | Targeting RNA-protein interactions with peptides and small molecule inhibitors | en |
dc.type | Text | de |
dc.contributor.referee | Dehmelt, Leif | - |
dc.date.accepted | 2024-01-18 | - |
dc.type.publicationtype | PhDThesis | de |
dc.subject.rswk | Scaffold <Biologie> | de |
dc.subject.rswk | Protein | de |
dc.subject.rswk | RNS-Bindung | de |
dc.subject.rswk | Epigenetik | de |
dc.subject.rswk | Inhibitor | de |
dc.subject.rswk | Peptid-Nucleinsäuren | de |
dc.subject.rswk | Struktur-Aktivitäts-Beziehung | de |
dc.subject.rswk | Non-coding RNA | de |
dcterms.accessRights | open access | - |
eldorado.secondarypublication | false | de |
Enthalten in den Sammlungen: | Chemische Biologie |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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Dissertation_Chang.pdf | DNB | 36.6 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource ist urheberrechtlich geschützt. |
Diese Ressource ist urheberrechtlich geschützt.
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