The quest for broad-spectrum coronavirus inhibitors

Abstract

The potential for zoonotic transmission and global spread demonstrated by the pandemic SARS-CoV-2, and its burden on public health, have emphasized the critical need to develop highly efficacious strategies for prophylaxis and therapy of infections with coronavirus at large. This thesis was largely dedicated to the search of coronavirus inhibitors by phenotypic cell-based screenings using different classes of compounds including immunosuppressive and non-immunosuppressive derivatives of cyclosporin A, hits from FDA-approved drug libraries and molecules synthesized by collaborators. Although, no effective therapies were found, this work warranted the further clinical investigation of a non-immunosuppressive compound in SARS-CoV-2-infected kidney transplant recipients, which is currently in progress. The development of antiviral therapies requires a detailed understanding of CoV replication and its interplay with host cells. Here, an in-depth characterization of the viral replicase subunit non-structural protein 14 provides evidence for its importance for virus viability and fitness, while establishing that nsp14 might be a good target for drug design with a potential pan-coronaviral activity spectrum. In the discussion, the history of unsuccessful CoV-targeting antivirals is briefly summarized, together with possible new approaches in antiviral research. Lastly, some prospects for future research are outlined.