Meyerhoff Graduate Fellows Program

Student Profiles

Jodian Brown
Chemistry and Biochemistry

Area of Doctoral Study: Biochemistry
Undergraduate Institute: University of the Sciences in Philadelphia

Research Advisor: Ian Thorpe, Ph.D.

Description of Research

RNA-dependent polymerases such as the hepatitis C virus (HCV) NS5B and human immunodeficiency virus reverse transcriptase (HIV-1 RT) are vital components of viral replication. Both proteins have been validated as targets for viral inhibition. In addition, there is no known mammalian homolog of NS5B, making it a critical target of HCV inhibition. Two of the major challenges of treating the hepatitis C virus are the emergence of resistance to current treatment regiments and co-infection with HIV, which can reduce the response to current HCV therapies. An approach to reducing the rate of drug resistance is to increase the inhibitory effect of small molecule inhibitors, which may be viable via the use of multiple ligands that target NS5B. Understanding the key protein-ligand interactions and changes in the free energy of the NS5B system upon ligand binding may highlight elements that are critical to an enhanced inhibitory effect in the presence of multiple ligands. This research project focuses on using multiple allosteric inhibitors and a combination of allosteric and pyrophosphate analogs. One approach to address co-infection, is to employ inhibitors that can simultaneously treat both viral infections. As such, the focus is on pyrophosphate analogs, which have exhibited micromolar activities against both HCV RdRp and HIV-1 RT. Knowledge of how these inhibitors are able to bind to both enzymes may provide information that can be used to optimize the inhibitory activity of these compounds against both viral polymerases. We are utilizing a computational chemistry approach to calculate the binding free energy and understand the dynamics when multiple ligands bind NS5B.
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