My laboratory uses methods drawn from biology and chemistry to study host-pathogen interactions at the molecular and pathway levels. We develop tools to precisely manipulate and monitor the infection of host cells by viruses and then use these tools to 1) understand how viruses perturb normal biochemical equilibria in the host cell, 2) define the consequences of these perturbations, and 3) exploit this knowledge in the design of therapeutic strategies to prevent disease associated with viral infection. Our current research models are hepatitis B virus (HBV), hepatitis C virus (HCV), and dengue virus (DENV) because they are scientifically interesting but, more importantly, because they are significant causes of human morbidity and mortality.
I. Small molecule inhibitors and RNAi: complementary tools for the discovery and characterization of cellular pathways utilized by DENV We are using small molecules and RNAi to identify the cellular pathways and potential pharmacological intervention points associated with DENV infection of the host cell. By screening libraries of known kinase inhibitors, we have shown that Abl and Src kinases play a critical role in dengue virus infection and are currently studying the mechanism(s) by which these kinases contribute to dengue biology as well as testing clinically approved kinase inhibitors as potential anti-DENV therapeutics in a murine model. We are using RNAi as a complementary method to identify host factors that are required for DENV infection and replication.
II. Discovery and development of novel small molecule inhibitors of DENV entry We are developing new small molecule tools that enable us to probe DENV processes within infected host cells. We recently discovered a novel class of small molecules that appear to inhibit dengue virus infection through action against a viral (versus a cellular) target and are using a combination of medicinal chemistry, biochemistry, and virology to characterize its detailed mechanism of action.
III. Lipidomics of viral infection A lipid envelope covers DENV, HBV, and HCV, and both DENV and HCV are known to replicate on membranous structures that are derived from the host cell. The biochemical mechanisms by which these membranous structures are induced are currently not known. In collaboration with the Saghatelian Lab, we are using LC-MS/MS methods to profile the full complement of lipids derived from virally infected versus mock-infected cells. The identification of metabolites that are differentially regulated during viral replication is expected to provide insights into key metabolic pathways that impinge upon viral replication and may ultimately lead to the identification of new drug targets,
IV. Directed evolution of HCV murine models A recurring theme in modern chemistry is the use of synthesis as a tool for understanding how natural systems work. De novo design and directed evolution of biological molecules has been used to understand mechanism and to engineer new function. We are applying these principles in vivo to develop a murine model of hepatitis C virus (HCV). We have hypothesized that HCV clones derived from human infections fail to replicate in mice because they cannot interact productively with the host cellular machinery required for replication and/or because they cannot evade an intracellular antiviral response. We have developed a novel system that permits us to perform forward genetics experiments in vivo to identify mutations that alleviate these restrictions. The goal of this work is the development of a murine model of HCV infection and replication that enables us (and others) to study the interaction between this virus and its host in the native liver of a genetically and immunogically well-defined animal.
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