Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Campagna, Matthew R.; Liu, Fei; Mao, Richeng; Mills, Courtney; Cai, Dawei; Guo, Fang; Zhao, Xiongyan; Ye, Hong; Cuconati, Andrea; Guo, Haitao; Chang, Jinhong; Xu, Xiaodong; Block, Timothy M.; Guo, Ju‐Tao

doi:10.1128/jvi.00582-13

Cited by 162 publications

(194 citation statements)

References 78 publications

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“…Long-term treatment of chronic hepatitis B with NUCs can lead to the emergence of drug-resistant HBV variants with specific mutations in the polymerase gene and result in treatment failure. Based on their distinct antiviral mechanism, all five previously reported chemotypes of capsid assembly modulators had been demonstrated to effectively inhibit the replication of NUC-resistant HBV (29,52). Not surprisingly, as shown in Table 2, BA-38017 inhibited the replication of wild-type HBV and mutant HBV bearing specific mutations in the polymerase gene conferring resistance to lamivudine, adefovir, and/or entecavir with similar efficacy.…”

mentioning

confidence: 93%

“…Entecavir (ETV) was provided by William S. Mason at Fox Chase Cancer Center, Philadelphia, PA. Bay 41-4109 was provided by Lai Wei at the Hepatology Institute of Beijing University, China. Sulfamoylbenzamides and benzamine derivatives used in this studies were synthesized in-house (29). 17-DMAG was purchased from InvivoGen.…”

Section: Methodsmentioning

confidence: 99%

“…While heteroaryldihydropyrimidines (HAPs), such as Bay 41-4109 and GLS4, misdirect capsid assembly to form noncapsid polymers of core proteins (25)(26)(27)(28), all other reported chemotypes of core protein assembly modulators induce the formation of various sizes of capsids devoid of viral pgRNA and DNA polymerase (29)(30)(31)(32). Structural biology studies suggest that HAPs, phenylpropenamides (PPAs), and sulfamoylbenzamides (SBAs) all bind to a hydrophobic pocket formed at the dimer-dimer interface near the C termini of core protein subunits, with contributions from two neighboring core protein dimers (33).…”

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confidence: 99%

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

Zhao

Zhang

et al. 2017

J Virol

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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.IMPORTANCE 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.KEYWORDS antiviral agents, capsid assembly, hepatitis B virus

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confidence: 93%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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

Zhao

Zhang

et al. 2017

J Virol

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“…Dengan mengganggu peran protein inti ini maka replikasi virus akan terhambat. Oleh karena itu protein inti VHB ini merupakan target yang sangat baik untuk pengembangan antivirus baru yang selektif, aman dan efektif (Bourne et al 2008;Campagna et al 2013;Klumpp et al 2015;Zlotnick et al 2015;Venkatakrishnan et al 2016). …”

Section: Pendahuluanunclassified

POTENSI SENYAWA BIOAKTIF TANAMAN GENUS <i>Phyllanthus</i> SEBAGAI INHIBITOR REPLIKASI VIRUS HEPATITIS B

Firdayani

Kusumaningrum

Miranti

2017

J Bioteknol Biosains Indones

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“…Most patients do not receive a long-term benefit from this therapy. As a result, significant effort has gone into the development of antiviral therapies that use small molecules to inhibit specific steps in virus replication, including virus uptake (Volz et al 2013), nucleocapsid assembly (e.g., Wu et al 2008;Campagna et al 2013), polymerase activity, and virus release (Noordeen et al 2013). Of these, only nucleoside analogs, which inhibit viral DNA synthesis, have been FDA-approved for use in humans.…”

Section: Animal Models and Antiviral Therapymentioning

confidence: 99%

Animal Models and the Molecular Biology of Hepadnavirus Infection

Mason

2015

Cold Spring Harbor Perspectives in Medicine

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Australian antigen, the envelope protein of hepatitis B virus (HBV), was discovered in 1967 as a prevalent serum antigen in hepatitis B patients. Early electron microscopy (EM) studies showed that this antigen was present in 22-nm particles in patient sera, which were believed to be incomplete virus. Complete virus, much less abundant than the 22-nm particles, was finally visualized in 1970. HBV was soon found to infect chimpanzees, gorillas, orangutans, gibbon apes, and, more recently, tree shrews (Tupaia belangeri) and cynomolgus macaques (Macaca fascicularis). This restricted host range placed limits on the kinds of studies that might be performed to better understand the biology and molecular biology of HBV and to develop antiviral therapies to treat chronic infections. About 10 years after the discovery of HBV, this problem was bypassed with the discovery of viruses related to HBV in woodchucks, ground squirrels, and ducks. Although unlikely animal models, their use revealed the key steps in hepadnavirus replication and in the host response to infection, including the fact that the viral nuclear episome is the ultimate target for immune clearance of transient infections and antiviral therapy of chronic infections. Studies with these and other animal models have also suggested interesting clues into the link between chronic HBV infection and hepatocellular carcinoma.

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Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Abstract: Chronic hepatitis B virus (HBV) infection

Cited by 162 publications

References 78 publications

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

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

POTENSI SENYAWA BIOAKTIF TANAMAN GENUS <i>Phyllanthus</i> SEBAGAI INHIBITOR REPLIKASI VIRUS HEPATITIS B

Animal Models and the Molecular Biology of Hepadnavirus Infection

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