Coinfection of HIV and HCV is a major public health threat and requires integrated therapeutic regimens. The cornerstones of antiretroviral therapy (ART) are nucleoside analogue inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) against HIV and ribonucleoside analog inhibitors (RAIs) against HCV. Despite several success cases, many compounds with similar chemical structures failed during clinical trials due to drug toxicity. Investigations have revealed that NRTIs' toxicity is mediated by mitochondrial DNA polymerase, Pol g, and RAIs cross-react with mitochondrial RNA polymerase (hmtRNAP), causing mitochondrial dysfunction. Mitochondria are vital to cellular activities; they supply energy to the cell, regulate cell cycle and cell death through apoptosis and participate in innate immunity. Our central hypothesis is that inhibition of human mitochondrial polymerases is a major cause of antiviral drug toxicity. The long-term goal of our research is to understand and overcome mitochondrial drug toxicity. We propose to reveal the structural and molecular mechanism for nucleoside-based antiviral drug mitochondrial toxicity by studying antiviral drug interactions with both human DNA and RNA polymerases.
Our specific aims i nclude 1) to reveal structural basis for Pol g's two-pronged defense against NRTIs and 2) to provide a mechanism for hmtRNAP mediated RAIs drug toxicity. The proposed studies will offer a comprehensive view for mitochondrial polymerases mediated antiviral drug toxicity, and provide insight in design of low-toxic antiviral reagents.
We will investigate the mechanisms HIV/HCV coinfection drug toxicity associated with interactions/inhibition of mitochondrial DNA and RNA polymerases using a combination of structural and functional methods. Structural studies will illustrate detailed drug interactions with the host protein at atomic resolution. The proposed studies will provide structural and molecular basis for two major polymerases mediated drug toxicities, and will significantly advance the rational design of potent and low toxicity inhibitors to combat co-infections by maximizing their affinity to the viral target while minimizing their interaction with human adverse reaction targets.
