Contact PD/PI: Guo, Ju-TaoTITLEEvaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitorsABSTRACTThis is a proposal to determine the feasibility and therapeutic benefits of newly discovered benzamidederivatives (BAs) as mono-therapeutic agents or in combination with nucleoside analogues for the treatment ofchronic 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 mechanisticallydistinct 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 genomereplication 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 immuneresponse and cccDNA function in the infected hepatocytes. Unlike other pgRNA encapsidation inhibitorsreported thus far, our benzamide pgRNA encapsidation inhibitors also effectively inhibit woodchuck hepatitisvirus (WHV), which allows for the evaluation of the therapeutic benefits of this class of antivirals in ahepadnavirus chronically infected animal model for the first time. We, therefore, propose in this project toperform further lead optimization, and advance compounds with the most favorable ADME, safety andpharmacokinetic (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 HBVnucleocapsid assembly and their consequential impacts on the interaction between HBV and its hosthepatocytes. At the completion of this project, we will have a better understanding of the potential clinicalbenefits of pgRNA encapsidation-targeted antiviral therapy, either alone or in combination with nucleosideanalogues in particular, and strategic insights in to the development of antiviral regimes for the cure of chronichepatitis B infection in general. A decision on further preclinical/clinical development of the lead BAscompounds will be made accordingly.Project Summary/Abstract Page 7

Public Health Relevance

Contact PD/PI: Guo; Ju-TaoPROJECT NARRATIVEThe goal of this proposal is to develop the newly discovered inhibitors of hepatitis B virus (HBV); benzamidederivatives; into a drug for the treatment of chronic hepatitis B. The drug candidate functions through disruptingthe assembly of viral nucleocapsids; which is mechanistically distinct from and should thus complement thecurrently FDA-approved antiviral medications. Hence; the drug may be of use by itself or in combination withcurrent medications to achieve extended clinical benefits.Project Narrative Page 8

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Koshy, Rajen
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Baruch S. Blumberg Institute
United States
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Zhao, Qiong; Hu, Zhanying; Cheng, Junjun et al. (2018) Hepatitis B Virus Core Protein Dephosphorylation Occurs during Pregenomic RNA Encapsidation. J Virol 92:
Alter, Harvey; Block, Timothy; Brown, Nathaniel et al. (2018) A research agenda for curing chronic hepatitis B virus infection. Hepatology 67:1127-1131
Zhao, Xuesen; Sehgal, Mohit; Hou, Zhifei et al. (2018) Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses. J Virol 92:
Guo, Fang; Zhao, Qiong; Sheraz, Muhammad et al. (2017) HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways. PLoS Pathog 13:e1006658
Liu, Yuanjie; Nie, Hui; Mao, Richeng et al. (2017) Interferon-inducible ribonuclease ISG20 inhibits hepatitis B virus replication through directly binding to the epsilon stem-loop structure of viral RNA. PLoS Pathog 13:e1006296
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:
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:
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
Liu, Bowei; Tang, Liudi; Zhang, Xiaohui et al. (2017) A cell-based high throughput screening assay for the discovery of cGAS-STING pathway agonists. Antiviral Res 147:37-46
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

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