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Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly
Journal article   Open access   Peer reviewed

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Shuo Wu, Qiong Zhao, Pinghu Zhang, John Kulp, Lydia Hu, Nicky Hwang, Jiming Zhang, Timothy M Block, Xiaodong Xu, Yanming Du, …
Journal of virology, v 91(16)
15 Aug 2017
DOI: https://doi.org/10.1128/JVI.00519-17
PMID: 28566379
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1212/WNL.0000000000002498View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open
url
https://doi.org/10.1128/JVI.00519-17View
Published, Version of Record (VoR) Open

Abstract

Anti-HIV Agents - isolation & purification Anti-HIV Agents - pharmacology Benzamides - isolation & purification Benzamides - pharmacology Capsid - metabolism Drug Discovery Drug Evaluation, Preclinical Hepatitis B virus - drug effects Hepatitis B virus - physiology Protein Binding Virus Assembly - drug effects
Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV. HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.

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43 citations in Web of Science
48 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Virology
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