This dissertation focuses on enhancing our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), measles virus (MeV), and Nipah virus (NiV). These viruses represent significant public health challenges, with the potential to cause long-term health issues and substantial economic impacts. By developing effective treatments that interrupt viral transmission, exploring how past infections influence current susceptibility, pinpointing drug targets, advancing our structural knowledge of viral proteins, and gaining deeper mechanistic insights into pathogen replication, we can reduce disease-related complications and healthcare costs.

The therapeutic efficacy of several treatments was evaluated using the ferret and Roborovski dwarf hamster models of severe COVID-19-like lung disease. These treatments included molnupiravir, Paxlovid-like nirmatrelvir/ritonavir, GS-621763 (an oral prodrug of remdesivir), 4’-fluorouridine (4’-FlU), EDP-235, and BioBlock (a neutralizing antibody targeting the spike protein delivered via nasal spray). In the ferret model, molnupiravir, GS-621763, EDP- 235, and BioBlock effectively prevented SARS-CoV-2 transmission between ferrets, while Paxlovid-like nirmatrelvir/ritonavir did not fully inhibit transmission. Additionally, 4’-FlU demonstrated strong antiviral activity against SARS-CoV-2 Wuhan lineage A and variants of concern (VOCs) alpha, delta, and gamma in ferrets, as well against RSV A in mice. In Roborovski dwarf hamsters, molnupiravir significantly reduced severe lung injury and viral lung titers for VOCs delta, gamma, and omicron. Similarly, Paxlovid-like nirmatrelvir/ritonavir reduced lung titers for VOCs delta and omicron in these hamsters.

This thesis also highlights the therapeutic potential of GHP-88309, a broad-spectrum paramyxovirus polymerase inhibitor, which can effectively counteract measles-like immune amnesia. It identifies an immune-priming mechanism that may explain the occurrence of bacterial superinfections following measles virus infection, offering insights that could reshape future treatment approaches for measles. Additionally, the thesis thoroughly evaluates the use of allosteric polymerase inhibitors as chemical probes to enhance the structural resolution of essential viral proteins. Furthermore, it expands our understanding of Nipah virus replication dynamics, revealing a promising target site for drug development.