The family Coronaviridae contains over forty distinct viruses, which cause a wide variety of disease in diverse hosts, ranging from severe enteric disease in pigs, to asymptomatic infection in bats. Although human coronaviruses were first identified over fifty years ago, there are currently no FDA approved therapeutics for coronavirus infection. Coronavirus disease outbreaks such as SARS, MERS, and the current COVID-19 pandemic illustrate the urgent need for both prophylactic and therapeutic treatments against these pathogens. Coronaviruses make use of spike (S), the largest known class I viral fusion protein, to both attach to host cells and to mediate the process of membrane fusion. Because of the critical role that S plays in the earliest stages of viral infection, it represents a clear target for the development of vaccines and immunotherapeutics. On the viral surface, S exists in a metastable prefusion conformation. Host-cell receptor binding gradually destabilizes this prefusion conformation, causing S to undergo dramatic conformational rearrangements that result in viral membrane fusion and the formation of the highly stable postfusion conformation. The first several chapters of this thesis describe the determination of structures of the S protein in the prefusion state and detail how these observations have been leveraged to design mutations to stabilize this conformation. These findings have important implications for vaccine development, and some of the preliminary results of their implementation are also described here. The second portion of this thesis describes potential immunotherapeutics, isolated using these stabilized coronavirus spikes. Several of these antibodies are capable of cross-neutralizing multiple coronaviruses and by determining their structures in complex with their viral targets, it was possible to elucidate their mechanisms of neutralization. Some of these antibodies and their derivatives are currently being investigated as potential therapeutics to combat the current COVID-19 pandemic and to help prevent future coronavirus outbreaks.
|Advisor:||McLellan, Jason S|
|Commitee:||Ackerman, Margaret, O'Toole, George, Veesler, David|
|School Location:||United States -- New Hampshire|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
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