Liganden- und Struktur-basiertes Design und Entwicklung potentieller eIF4A-Inhibitoren

Seit Beginn des 21. Jahrhunderts kam es bereits wiederholt zu großen Ausbrüchen, die durch RNA-Viren (EBOV, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Zika-Virus) ausgelöst wurden. So stellte die Ebola Epidemie 2014 in Westafrika und die aktuelle COVID-19-Pandemie (coronavirus disease 2019) eine globale Bedr...

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Bibliographic Details
Main Author: Pham, Thi Lan Phuong
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2021
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Since the beginning of the 21st century, there have been repeated large outbreaks caused by RNA viruses (EBOV, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Zika virus). The Ebola epidemic in West Africa in 2014 and the ongoing COVID-19 pandemic (coronavirus disease 2019) represent a global threat to humanity and highlight the need for antiviral drugs to combat the current and future pandemics. Due to the high mutation rate of RNA viruses, the risk of developing resistance through new variants is always present, since RNA viruses can quickly adapt to new conditions. In this case, the inhibition of virus-specific proteins could lead to a loss of the efficacy of antiviral drugs. Addressing host factors with antiviral drugs, on the other hand, could minimize the risk of this resistance development. One promising target is the DEAD-box helicase eIF4A which is used by different RNA viruses for the translation of their viral proteins. As a natural eIF4A inhibitor, Silvestrol in particular is a very interesting target because it inhibits a broad spectrum of RNA viruses in a nanomolar range. Considering its potential as antiviral drug, it could also be used to treat new emerging viruses. An disadvantage is its complex structure and the resulting difficult synthesis. Therefore, this thesis focuses on the development of small molecules that have a similar structure and inhibition as Silvestrol, but are more drug-like. The main focus of this thesis was the synthesis of novel eIF4A-inhibitors by using a ligand and structure-based design with spotlight on two substance classes, sulfonamides and N-acylamino acid amides. From repetitive cycles of synthesis, testing and optimization through modifications of different components of the starting structures, important findings for the further development of the structures were drawn. The linear sulfonamides, based on a previous work, were optimized with the inclusion of molecular docking to obtain branched sulfonamides. Thereby, the unspecific inhibitory effect of the linear sulfonamides could be improved to a specific inhibitory effect. Compounds with a specific inhibitory effect on the translation were also identified among the N-acylamino acid amides resulting from a rational design. Two promising compounds derived from these two substance classes even showed an antiviral effect against the coronaviruses HCoV-229E and SARS-CoV-2, while another compound showed activity against the Rift Valley Fever Virus. Finally, the basis for future work in the field of N-acylamino acid amides and branched sulfonamides could be laid in the present dissertation.