This is a proposal to determine the feasibility and therapeutic benefits of newly discovered benzamide derivatives (BAs) as mono-therapeutic agents or in combination with nucleoside analogues for the treatment of chronic hepatitis B. BAs were identified in our laboratory as inhibitors of hepatitis B virus (HBV) pregenomic (pg) RNA encapsidation, which is essential for the subsequent viral DNA synthesis. They are mechanistically distinct from, and should thus complement, the currently FDA-approved antiviral medications. In addition, inhibition of pgRNA encapsidation, or the nucleocapsid assembly, should not only preclude HBV genome replication and virion production, it might also disrupt the metabolism of HBV pgRNA-reverse transcriptase (RT) complex and core protein, which could consequentially interfere with the host innate antiviral immune response and cccDNA function in the infected hepatocytes. Unlike other pgRNA encapsidation inhibitors reported thus far, our benzamide pgRNA encapsidation inhibitors also effectively inhibit woodchuck hepatitis virus (WHV), which allows for the evaluation of the therapeutic benefits of this class of antivirals in a hepadnavirus chronically infected animal model for the first time. We, therefore, propose in this project to perform further lead optimization, and advance compounds with the most favorable ADME, safety and pharmacokinetic (PK) profiles for antiviral efficacy study in the WHV-infected woodchucks in vivo. Meanwhile, we will continue our efforts toward understanding the molecular mechanism by which BAs inhibit HBV nucleocapsid assembly and their consequential impacts on the interaction between HBV and its host hepatocytes. At the completion of this project, we will have a better understanding of the potential clinical benefits of pgRNA encapsidation-targeted antiviral therapy, either alone or in combination with nucleoside analogues in particular, and strategic insights in to the development of antiviral regimes for the cure of chronic hepatitis B infection in general. A decision on further preclinical/clinical development of the lead BAs compounds will be made accordingly.
The goal of this proposal is to develop the newly discovered inhibitors of hepatitis B virus (HBV), benzamide derivatives, into a drug for the treatment of chronic hepatitis B. The drug candidate functions through disrupting the assembly of viral nucleocapsids, which is mechanistically distinct from and should thus complement the currently FDA-approved antiviral medications. Hence, the drug may be of use by itself or in combination with current medications to achieve extended clinical benefits.
|Wu, Shuo; Zhao, Qiong; Zhang, Pinghu et al. (2017) Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly. J Virol 91:|
|Guo, Fang; Tang, Liudi; Shu, Sainan et al. (2017) Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus. Antimicrob Agents Chemother 61:|
|Tang, Liudi; Zhao, Qiong; Wu, Shuo et al. (2017) The current status and future directions of hepatitis B antiviral drug discovery. Expert Opin Drug Discov 12:5-15|
|Zhang, Pinghu; Liu, Fei; Guo, Fang et al. (2016) Characterization of novel hepadnaviral RNA species accumulated in hepatoma cells treated with viral DNA polymerase inhibitors. Antiviral Res 131:40-8|
|Qi, Yonghe; Gao, Zhenchao; Xu, Guangwei et al. (2016) DNA Polymerase ? Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus. PLoS Pathog 12:e1005893|
|Cui, Xiuji; Clark, Daniel N; Liu, Kuancheng et al. (2016) Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes. J Virol 90:486-96|
|Guo, Fang; Han, Yanxing; Zhao, Xuesen et al. (2015) STING agonists induce an innate antiviral immune response against hepatitis B virus. Antimicrob Agents Chemother 59:1273-81|
|Yan, Ran; Zhao, Xuesen; Cai, Dawei et al. (2015) The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion. J Virol 89:9200-12|
|Chang, Jinhong; Block, Timothy M; Guo, Ju-Tao (2015) Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections. Antivir Ther 20:257-9|
|Chang, Jinhong; Guo, Ju-Tao (2015) Treatment of chronic hepatitis B with pattern recognition receptor agonists: Current status and potential for a cure. Antiviral Res 121:152-9|
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