From repurposed drugs to pan-enterovirus and rhinovirus inhibitors

Abstract

Continuous discovery and development of new antiviral medications and vaccines are of great importance for global health. This process is particularly important for viruses without current therapy or circulating viruses that gained resistance towards existing antivirals. EV include many important human pathogens and are the causative agent of mild and more severe disease, which can require hospitalizations especially in small children and immunocompromised individuals. Currently, there are no antivirals 1 licensed to treat EV infections. Over the decade, several direct-acting inhibitors have been developed. An overview of these inhibitors is given in chapter 2. In this thesis, we focused on the identification of potential new avenues for anti-EV drug development. In chapter 2, an overview of direct-acting and host-targeting inhibitors, including repurposed drugs, is given. One of these repurposed drugs is ITZ, which was identified as potent inhibitor of enterovirus replication by targeting the lipid shuttling protein OSBP. In chapter 3, we set out to investigate the important pharmacophoric properties responsible for the antiviral activity to decouple its different pharmacological activities in order to reduce possible side-effects. chapter 4 provides new insight into the mode-of action of another repurposed drug, the SSRI fluoxetine which targets the enterovirus 2C protein. We used a combination of virological methods, biochemistry and computational modeling to investigate the stereochemistry. These studies resulted in the identification of a potential binding pocket in 2C. In chapter 5, we conducted a SAR study on fluoxetine to establish the pharmacophoric features underlying its antiviral activity. In chapter 6, we performed a SAR study to investigate the antiviral activity of the recently identified CV-B3 inhibitor N-(4-fluorobenzyl)-N-(4-methoxyphenyl)furan- 2-carboxamide, which contains a chemical backbone that resembles that of fluoxetine. Further, we provided valuable insight into a common mechanism of resistance development in 2C towards 2C inhibitors. In chapter 7, the results of this thesis are summarized and their implications are discussed.