Authors: Stenbratt, Carl Leonard
Title: RNA degradation using small molecule-based recruiters of RNase L
Language (ISO): en
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.
Subject Headings: Targeted RNA degradation
Bifunctional molecule
Molecular glue
RNase L activator
WDR5 inhibitor
TAR RNA ligand
RNA-binding protein
Small molecules interacting with RNA
Small molecule
Organic chemistry
Subject Headings (RSWK): RNA
Issue Date: 2021
Appears in Collections:Chemische Biologie

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