Development of a New HIV Treatment

Yu Zhang is a Senior double majoring in Biology and Chemistry. She was awarded a Spring 2019 Conference Grant which she used to attend the National Conference on Undergraduate Research.

In NCUR conference, I presented my research on the development of a new HIV treatment. I was very happy to talk with many scholars who were also dedicated in natural science research. According to the previous report, over 170 million people infected worldwide, the hepatitis C virus (HCV) represents a significant public health burden. The primary mode of transmission for HCV is via exposure to infected blood, including transfusions from infected donors, and through intravenous use of illicit drugs. Although a minority of all HCV infections will spontaneously resolve without any clinical outcome, an estimated 80% of cases will progress into chronic hepatitis. The need for the treatment of hepatitis C virus (HCV), has provided considerable impetus for the development of new classes of antiviral drugs such as nucleoside analogues. Hepatitis C contains a single, positive-strand RNA genome that encodes only one open reading frame translated to a polyprotein of approximately 3,000 amino acids.

Ribonucleotide analog inhibitors of the RNA-dependent RNA polymerase of hepatitis C virus (HCV) are important development in HCV antiviral therapy.The NS5B protein acts as the RNA-dependent RNA polymerase, with critical functions in RNA replication and transcription. Several nucleotide analogs inhibiting HCV NS5B can enter liver cells as non-phosphorylated nucleosides before being converted to the active triphosphates by cellular kinases. They can compete with the natural substrate for incorporation into viral RNA and cause chain termination. I want to develop strategies to rationally and effectively screen for high-potency antiviral nucleosides, which will facilitate the future HCV drug design. 

Since Our hypothesis is that Triphosphate Hydrolysis is Homologous and endo-exo Equilibrium of RNA governs antiviral activityIn this study, I focused on 16 nucleosides analogues and their activities against HCV polymerase. We performed molecular modeling studies based on the X-ray structure of 4WTA, a HCV polymerase, and looked for the relationship between structural conformations of nucleoside analogues and activities against HCV polymerase.  

 

To investigate the effect of the structure conformation on the activity of the nucleoside, we used a comprehensive high level DFT/B3LYP QM/MM theoretical method and docking techniques. By using docking, we captured the binding position of the nucleotides in the active site, but there was a weak relationship between docking score and antiviral activity of the nucleoside analogues. We also calculated the differences of density functional theory (DFT) energy of Endo and Exo conformers of the nucleoside analogues.  The difference correlates well with the antiviral activity. To our knowledge, these results provide an effective way to use geometry to predict the activity of antiviral nucleoside analogues against HCV polymerase.

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