Characterizing Chemical Tools for the Discovery of Novel Antiviral Therapeutics

Abstract

Despite our growing knowledge of virus biology they continue to present a problem to global public health. This problem arises from their high mutation rates that allow them to evade antiviral therapies that we have developed to date. An alternative solution for developing antiviral therapies could be to target host cell factors that are hijacked by the virus. The basis of this hypothesis is that if we can stop the virus from using host cell machinery or from evading host immune mechanisms we could treat the infection more efficiently. With the major research focus being on viral proteins and how we can prevent their functions, there is a lot of work to be done in finding host factors that could be the key to treating an infection. The three themes presented in this thesis broadly focus on this goal. The first theme looks at miRNAs, their interacting partners, and their dysregulation during HCV infection. A microRNA is identified from a small molecule screen of miRNAs that are dysregulated during HCV infection and its role in liver immunometabolism is examined to determine its antiviral potential and identify host factors that could be of interest to target with antiviral therapeutics. The second theme examines the potential of activity-based protein profiling techniques for complementing existing antiviral therapies. An azauracil probe is characterized to examine its ability to interact with viral polymerases and its suitability as a building block for antiviral research or therapies. The final theme uses activity-based protein profiling techniques to study a novel carbamate-hydrazone chemotype and establish its suitability as a chemical probe. The hydrazone probe’s reactivity with the mammalian proteome was determined and its interacting partners were identified using chemoproteomic techniques with an overall goal of examining its suitability for antiviral research. Overall, this thesis uses chemical and molecular biology techniques to present three differing perspectives on how to approach the discovery of host factors and develop novel antiviral therapies.