| dc.contributor.advisor | Thomas, Franziska Prof. | |
| dc.contributor.author | Schirmacher, Robert Heinz Erich | |
| dc.date.accessioned | 2021-06-25T13:25:06Z | |
| dc.date.available | 2021-07-02T00:50:07Z | |
| dc.date.issued | 2021-06-25 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-587D-A | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8689 | |
| dc.language.iso | eng | de |
| dc.publisher | Niedersächsische Staats- und Universitätsbibliothek Göttingen | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 540 | de |
| dc.title | Design and synthesis of small organic molecules to stabilize ALS-associated SOD1 mutants | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Thomas, Franziska Prof. Dr. | |
| dc.date.examination | 2021-05-07 | |
| dc.description.abstracteng | Amyotrophic Lateral Sclerosis is a globally occurring neurodegenerative disease with serious implications for the patient’s life as well as imposing a heavy economic burden both on the affected individuals and society. Due to higher exposure to risk factors and an increasing lifespan, total costs of Amyotrophic Lateral Sclerosis are expected to rise drastically in the near future. Since there are no causal treatments known and currently available medications only alleviate symptoms, more research in interdisciplinary fields of science is necessary.
This thesis focuses on the familiar type of Amyotrophic Lateral Sclerosis, more specifically the disease-induced aggregation of the well-studied protein Superoxide Dismutase 1, whose mutations account for 10-20 % of all ALS incidents in familiar Amyotrophic Lateral Sclerosis. Dissociation of SOD1 into aggregation prone monomers is currently viewed as one of the most important triggers for neuronal death. It is envisaged to stabilize the homodimer structure of the protein with a small molecule through an affinity-based approach in order to prevent aggregation and to restore the catalytic activity of pathological mutants. Using in silico design, several lead structures are elaborated as potential lead structures for protein-ligand binding. Upon rational variation of these structures, a small molecular library is synthesized to verify the computational results with biophysical techniques. After expression and purification of the protein, methods such as Isothermal Titration Calorimetry, Fluorescence Anisotropy, Microscale Thermophoresis as well as X-Ray Diffraction of protein-ligand-complex crystals are employed to obtain information about the biophysical properties of the synthesized ligands. It is demonstrated that some of the aforementioned small molecules show affinity-based binding to the protein of interest. Facile synthetic pathways to these molecules and strategies for their variation are outlined.
The significance of this work is that it expounds a rational approach for the development of novel, structurally diverse small molecules that exhibit the ability to bind the Superoxide Dismutase 1 in an affinity-based binding mode. | de |
| dc.contributor.coReferee | Alcarazo, Manuel Prof. Dr. | |
| dc.contributor.thirdReferee | Diederichsen, Ulf Prof. Dr. | |
| dc.contributor.thirdReferee | Frauendorf, Holm Dr. | |
| dc.contributor.thirdReferee | Bennati, Marina Prof. Dr. | |
| dc.contributor.thirdReferee | Tittmann, Kai Prof. Dr. | |
| dc.subject.eng | ALS, SOD1 | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-587D-A-0 | |
| dc.affiliation.institute | Fakultät für Chemie | de |
| dc.subject.gokfull | Chemie (PPN62138352X) | de |
| dc.description.embargoed | 2021-07-02 | |
| dc.identifier.ppn | 1761310305 | |