RNA degradation using small molecule-based recruiters of RNase L

Stenbratt, Carl Leonard

RNA degradation using small molecule-based recruiters of RNase L

dc.contributor.advisor	Waldmann, Herbert
dc.contributor.author	Stenbratt, Carl Leonard
dc.contributor.referee	Brunschweiger, Andreas
dc.date.accepted	2021-10-28
dc.date.accessioned	2021-11-18T07:23:29Z
dc.date.available	2021-11-18T07:23:29Z
dc.date.issued	2021
dc.description.abstract	The human genome is mainly transcribed into non-coding RNAs that are not translated into proteins. With increasing understanding of function through continued research it has become evident that parts of the transcriptome are disease-related. RNAs are becoming increasingly important targets for the development of novel medicines using chemical modalities such as small molecules, bifunctional molecules, peptides, oligonucleotides and conjugates. Yet only part of what is possible to achieve by targeting non-coding RNAs has been discovered, which allows for the development of therapeutics with novel mode of actions beyond current drugs. Described in this thesis are strategies targeting RNAs for catalytic degradation. The design, synthesis, characterization and biochemical evaluation of both 2-aminothiophene-containing heterocyclic molecules and thiophenones identified a suitable compound class for activation of RNase L. Development of the novel RITAC strategy was based on chemical conjugates, containing thiophenones, for targeted degradation of the RNA interactome of RNA-binding proteins via recruitment of RNase L. The RNA-binding protein WDR5 was used in a proof-of-concept study, where obtained heterobifunctional molecules, targeting an allosteric binding site within WDR5, may serve to identify new protein-RNA interactions and to develop therapeutics for the treatment of acute myeloid leukemia. Additionally, the scope of the RIBOTAC strategy was expanded using thienopyridines to recruit RNase L for degradation of the HIV-1 RNA genome by binding to the transactivation response element. Obtained heterobifunctional molecules may serve as therapeutics for the treatment of HIV-1 infections.	de
dc.identifier.uri	http://hdl.handle.net/2003/40562
dc.identifier.uri	http://dx.doi.org/10.17877/DE290R-22431
dc.language.iso	en	de
dc.subject	Targeted RNA degradation	de
dc.subject	Bifunctional molecule	de
dc.subject	Molecular glue	de
dc.subject	RNase L activator	de
dc.subject	WDR5 inhibitor	de
dc.subject	TAR RNA ligand	de
dc.subject	RNA-binding protein	de
dc.subject	Small molecules interacting with RNA	de
dc.subject	Small molecule	de
dc.subject	Organic chemistry	de
dc.subject.ddc	570
dc.subject.ddc	540
dc.subject.rswk	RNA	de
dc.subject.rswk	RNA-Bindungsproteine	de
dc.title	RNA degradation using small molecule-based recruiters of RNase L	de
dc.type	Text	de
dc.type.publicationtype	doctoralThesis	de
dcterms.accessRights	open access
eldorado.secondarypublication	false	de

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