Dokument: Investigating the capacity of locked nucleic acid mixmer antisense oligonucleotides to inhibit viral replication
| Titel: | Investigating the capacity of locked nucleic acid mixmer antisense oligonucleotides to inhibit viral replication | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=60998 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20221024-130538-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Ostermann, Philipp Niklas [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Schaal, Heiner [Gutachter] Prof. Dr. Feldbrügge, Michael [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Efficacious antiviral agents are still rare and typically only available against viral diseases of high public interest. Therefore, finding novel antiviral agents or antiviral strategies remains a high priority. Antisense oligonucleotides (ASOs) can be used for a variety of applications, including molecular diagnostics, as tools for basic research or for therapeutic applications. Thanks to improved chemical modifications and better characterization of their functions, more therapeutic ASOs are now being tested in clinical trials with some already approved. However, there are still vast knowledge gaps concerning general ASO function, for instance, their efficacy in different cell types or ASO-induced effects on target RNA with respect to the rates of cytoplasmic and nuclear activity. Despite such gaps, a previous study indicated the capacity of locked nucleic acid mixmer-modified antisense oligonucleotides (LNA mixmers) to inhibit HIV-1 replication in cell culture. To investigate whether such LNA mixmers can also interfere with RNA viruses replicating in the cytoplasm, this thesis investigates whether unassisted LNA mixmer delivery can inhibit replication of SARS-CoV-2. To do this, infectious SARS-CoV-2 was first isolated from a naso-/oropharyngeal swab specimen to establish a valid infection model. The delivered anti-SARS-CoV-2 LNA mixmers, however, failed to inhibit viral replication in subsequent infection experiments. To exclude that induction of double membrane vesicles is a reason for the unexpected failure of LNA mixmer activity against SARS-CoV-2, LNA mixmer-mediated inhibition was tested against Hazara virus. Hazara virus is considered a surrogate model for the highly lethal Crimean-Congo hemorrhagic fever virus, and it has not been described to induce double membrane vesicles. Since there was no antiviral LNA mixmer activity against this second RNA virus, which also replicates in the cytoplasm, a possible high susceptibility of splicing regulatory elements, which were targeted while successfully inhibiting HIV-1 replication, was analyzed using the nuclear replicating Influenza A virus. However, even the LNA mixmers against Influenza A virus did not exhibit any observable antiviral activity. Besides their diverse replication mechanisms, however, the analyzed viruses also differ in their host cells. By analyzing HIV-1 inhibition in different cell models, it became apparent that T-cells are particularly susceptible to ASO activity compared to other cell types. This key finding might thus explain the apparent lack of antiviral LNA mixmer activity against SARS-CoV-2, Hazara virus and Influenza A virus, all of which do not replicate in T-cells. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Mikrobiologie | |||||||
| Dokument erstellt am: | 24.10.2022 | |||||||
| Dateien geändert am: | 24.10.2022 | |||||||
| Promotionsantrag am: | 04.07.2022 | |||||||
| Datum der Promotion: | 20.10.2022 |
