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Modulation of Survivin's cancer-promoting functions with supramolecular ligands
Survivin is highly upregulated in most cancers and has been associated with a resistance against chemo- and radiotherapy and a poor clinical outcome. The protein is considered to be a key player of carcinogenesis due to its anti-apoptotic function and its role in cell proliferation. As it is mainly expressed during embryonic development but mostly absent in terminally differentiated adult tissues, it might be one of the most cancer-specific proteins identified so far. Survivin possesses no enzymatic activity, which makes it challenging to address the protein as a drug target. Various strategies so far have included antisense oligonucleotides, siRNAs, small molecule inhibitors, gene therapy and immunotherapy but none of these approaches has yet reached the clinic. This thesis aimed to explore a novel approaches by targeting protein-protein interactions of Survivin and its functionally relevant binding partners. Supramolecular ligands based on the guanidiniocarbonyl pyrrole cation served as highly specific anion binders in order to target respective anionic hot spots on the surface of the protein. Ligand MM138 was designed to interfere with the interaction between Survivin and Histone H3, which is essential for Survivin to fulfil its role in cell proliferation. The binding of MM138 to Survivin’s Histone H3 binding site could be verified by NMR analyses. In addition, the establishment of several microscopic and cellular assays allowed it to be demonstrated that the supramolecular ligand is able to inhibit Survivin-Histone H3 interaction inside the cell and thereby reduce cancer cell proliferation. Ligand DA162 aimed to target the interaction between Survivin and its export receptor Crm1, which is not only relevant for Survivin’s Crm1-mediated nuclear export into the cytoplasm where it acts as an inhibitor of apoptosis, but also for its role within the chromosomal passenger complex during mitosis. It could be shown that DA162 binds to Survivin with a low micromolar KD and is able to inhibit the interaction between ...
Modulation of Survivin's cancer-promoting functions with supramolecular ligands
Survivin is highly upregulated in most cancers and has been associated with a resistance against chemo- and radiotherapy and a poor clinical outcome. The protein is considered to be a key player of carcinogenesis due to its anti-apoptotic function and its role in cell proliferation. As it is mainly expressed during embryonic development but mostly absent in terminally differentiated adult tissues, it might be one of the most cancer-specific proteins identified so far. Survivin possesses no enzymatic activity, which makes it challenging to address the protein as a drug target. Various strategies so far have included antisense oligonucleotides, siRNAs, small molecule inhibitors, gene therapy and immunotherapy but none of these approaches has yet reached the clinic. This thesis aimed to explore a novel approaches by targeting protein-protein interactions of Survivin and its functionally relevant binding partners. Supramolecular ligands based on the guanidiniocarbonyl pyrrole cation served as highly specific anion binders in order to target respective anionic hot spots on the surface of the protein. Ligand MM138 was designed to interfere with the interaction between Survivin and Histone H3, which is essential for Survivin to fulfil its role in cell proliferation. The binding of MM138 to Survivin’s Histone H3 binding site could be verified by NMR analyses. In addition, the establishment of several microscopic and cellular assays allowed it to be demonstrated that the supramolecular ligand is able to inhibit Survivin-Histone H3 interaction inside the cell and thereby reduce cancer cell proliferation. Ligand DA162 aimed to target the interaction between Survivin and its export receptor Crm1, which is not only relevant for Survivin’s Crm1-mediated nuclear export into the cytoplasm where it acts as an inhibitor of apoptosis, but also for its role within the chromosomal passenger complex during mitosis. It could be shown that DA162 binds to Survivin with a low micromolar KD and is able to inhibit the interaction between ...
Modulation of Survivin's cancer-promoting functions with supramolecular ligands
Vallet, Cecilia (author) / Knauer, Shirley
2023-10-25
Theses
Electronic Resource
English
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