Inhibition of measles virus replication by proteasome inhibitor Argyrin F constituting a novel virostatic compound

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Dokumentart: PhDThesis
Date: 2022-02-01
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Lauer, Ulrich (Prof. Dr.)
Day of Oral Examination: 2021-12-21
DDC Classifikation: 610 - Medicine and health
Other Keywords:
Antiviral drug
Argyrin F
Measles virus
Proteasome inhibitor
Virostatic compound
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In contrast to the pathogen causing smallpox (Variola virus), the measles virus has not yet been eradicated, despite the availability of effective vaccines. On the contrary, in recent years there has been a significant increase of reported cases, reaching its worldwide peak with more than 850,000 cases in 2019. Most fatal cases occur in children under the age of 5. Therefore, further measures in dealing with the virus are urgently needed. One of these is the expansion of therapeutic options to generate and license a first-in-class measles specific antiviral drug. So far in addition to prevention through vaccination, only supportive therapies have been available such as rehydration, vitamin A substitution or the treatment of secondary bacterial infections. By searching for antitumorigenic synergisms between small molecule agents and recombinant measles vaccine virus virotherapeutics, our working group surprisingly found, when using the proteasome inhibitor Argyrin F in combination with measles vaccine virus, in contrast to the assumed increased anti-tumor effect, a reduced oncolysis. Follow-up experiments showed a clear reduction of measles virus titers when applying this combined therapy. We hypothesized that Argyrin F could represent a completely unknown potent novel antiviral drug against measles. The aim of this dissertation was to better evaluate the possible clinical application of Argyrin F as an antiviral agent in measles. In this context, it was necessary to confirm the antiviral effect and to characterize it precisely. In this dissertation it was found that Argyrin F strongly inhibited replication of the measles vaccine virus MeV-GFP. The virostatic effect was dose-dependent up to a minimum effective dose of 0.1 µg/ml Argyrin F. Furthermore, it was dependent on the time point of application before/after infection with measles viruses. We found that Argyrin F can inhibit measles vaccine virus replication when given up to 24 hours after infection. The potent virostatic effect could also be demonstrated in another 3 out of 4 measles vaccine virus strains tested. In contrast, depending on the genotype, measles wild-type viruses could only be inhibited weakly or not at all. Further approaches are necessary to elucidate the molecular mechanism of the virostatic effect of Argyrin F. Summing up Argyrin F in its current form cannot yet be considered for clinical application against wildtype measles viruses. At the required therapeutic dosage, a cytotoxic effect still occurs making the occurrence of serious side effects possible. In addition, depending on the genotype of wild-type measles viruses, virus titers were reduced only weakly or not at all. Further adaptations of the molecule by medicinal chemistry are therefore necessary. In contrast, use of Argyrin F in virotherapy, employing only measles vaccine viruses, as a medical intervention for excessively replicating measles virus based virotherapeutics seems to be promising.

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