Y. Whitney Yin
The University of Texas Medical Branch
Will be updated soon!
Structural and functional studies of antiviral drug toxicity Antiviral drugs based on nucleoside analogs are effective inhibitors for viral reverse transcriptase and RNA polymerase, thus have been successfully used in treating HIV and HCV infections. With prolonged patients life span, the success of the drugs now has to be balanced with their drug toxicity. One of the major target of nucleoside analogs is human mitochondrial DNA polymerase, Pol Y. Because drug efficacy is not completely correlated with drug toxicity, we believe there is exploitable difference in designing potent, low toxic antiviral reagents. To reveal the structural differences between viral target protein and human adverse reaction target, we embarked on structural and functional studies of replicating human mitochondrial DNA polymerase or stalled by antiviral drugs. My laboratory determined the first crystal structures of human Pol Y holoenzyme. Recently, we determined structures of ternary complex of Pol Y-DNA with a substrate or an antiHIV reagent, zalcitabine, lamivudine or emtricitabine. These structures provided unprecedented insight in Pol Y mediated antiviral drug toxicity. As Pol Y mutations are associated with multisystem disorders, the structures have been widely used by basic scientists as well as clinicians to understand the detrimental effects of the mutations.