Nucleoside analog reverse transcriptase inhibitors (NRTIs) were the first therapeutic agents to demonstrate clinical efficacy for HIV-1 infection, and continue to be the cornerstone of highly active antiretroviral therapy (HAART) for HIV-1. Host factors play important roles in susceptibility to antiviral agents such as NRTIs;deoxynucleoside triphosphate (dNTP) pool size and DNA exonuclease, TREX-1, are of particular interest based on our preliminary results. Our laboratory recently discovered a new NRTI, 4'-ethynylstavudine (4'-Ed4T). 4'- Ed4T has much better therapeutic index in cell culture than either zidovudine (AZT) or stavudine (D4T). The active metabolites of 4'-Ed4T have longer intracellular half lives and we have had difficulty in generating highly resistant HIV virus to 4'-Ed4T in culture. We hypothesize that 4'-Ed4T may present a higher genetic barrier to the development of highly drug resistance mutations. It is currently under Phase Ib/2a clinical trial and has demonstrated impressive anti-HIV effect. The main objectives of this application are to study two host factors that may affect the efficacy of NRTIs and to characterize resistance to 4'-Ed4T. We propose the three specific aims: 1. Determine the role of intracellular dNTP content on the anti-HIV activity of selected NRTIs. 2. Explore the role of cytoplasmic Exo, TREX-1, in HIV antiviral activity of NRTI and HIV replication. 3. Explore the evolution of 4'-Ed4T resistant HIV and characterization of the resistant virus.
The Specific Aim 1 will develop a more reliable, sensitive, and time saving method to address the role of endogenous dNTP in determining NRTI activity.
Specific Aim 2 will also explore the potential role of TREX-1 in NRTI antiviral activity and HIV replication. Future HAART protocols could take into consideration the difference in TREX-1 expression in target cells of individuals to avoid individual variation in response to some NRTIs. The studies proposed will provide information on why it is difficult to develop resistance to 4'-Ed4T and the behaviors of the highly resistant virus to 4'-Ed4T. This will help in the clinical development of 4'-Ed4T;either as a single drug or as part of a simplified HAART.
Host Factors affecting antiviral activity of HIV nucleoside analogs, HIV replication and novel mechanism of resistant to a new anti-HIV compound, 4'-Ed4T.
|Wang, Ying; Lam, Wing; Chen, Shao-Ru et al. (2016) Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70. Sci Rep 6:32832|
|Tsao, Ning; Lee, Ming-Hsiang; Zhang, Wei et al. (2015) The contribution of CMP kinase to the efficiency of DNA repair. Cell Cycle 14:354-63|
|Wu, Chien-Huang; Wang, Chuan-Jen; Chang, Chun-Ping et al. (2015) Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors. J Med Chem 58:1452-65|
|Fan, Jiyun; Wang, Ying; Xiong, Hui et al. (2014) Impact of the rtI187V polymerase substitution of hepatitis B virus on viral replication and antiviral drug susceptibility. J Gen Virol 95:2523-30|
|Selvaraj, S; Ghebremichael, M; Li, M et al. (2014) Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-Î³ inhibition. Clin Pharmacol Ther 96:110-20|
|Haraguchi, Kazuhiro; Takeda, Shingo; Kubota, Yutaka et al. (2013) From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir. Curr Pharm Des 19:1880-97|
|Tsou, Lun K; Chen, Chin-Ho; Dutschman, Ginger E et al. (2012) Blocking HIV-1 entry by a gp120 surface binding inhibitor. Bioorg Med Chem Lett 22:3358-61|
|Tsou, Lun K; Cheng, Yao; Cheng, Yung-Chi (2012) Therapeutic development in targeting protein-protein interactions with synthetic topological mimetics. Curr Opin Pharmacol 12:403-7|
|Haraguchi, Kazuhiro; Shimada, Hisashi; Kimura, Keiogo et al. (2011) Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI. ACS Med Chem Lett 2:692-697|
|Esposito, Francesca; Kharlamova, Tatyana; Distinto, Simona et al. (2011) Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases. FEBS J 278:1444-57|
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