Design, Synthesis, and Biological Evaluation of Triazolo-pyrimidine Derivatives as Novel Inhibitors of Hepatitis B Virus Surface Antigen (HBsAg) Secretion

“…pCMV-HBV expressing HBV pgRNA under the control of the cytomegalovirus (CMV) immediate early promoter, wild-type HBV replicon pHBV1.3mer, and pCMV-HBV-Δpol have been described previously (72)(73)(74). The pTRE2-derived plasmids containing a wild-type or mutant HBV genome in DNA polymerase gene, including pTREHBV, pTREHBV/rtA180V, pTREHBV/rtN236T, pTREHBV/rtM204I, pTREHBV/rtL180M, and pTREHBV/rtL180M/rtM204V/rt184G/rtS202I, were constructed and reported previously (71,75). Information on the sequence and construction of the wild-type or NUC-resistant HBV genotype B and C plasmids, including pHY536207, pHY634, pHY6923, and pHY6945, has been published previously (76).…”

Section: Methodsmentioning

confidence: 99%

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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“…Therefore, HBF-0259 could be introduced as an effective receptor blocker with probable negative influence on AAs presented in interaction site within CypA NP not possible recognition, binding and penetration of HBV to the host cell with therapeutic benefits by blocking SCCA1. The HBF-0259 mechanism of effect on HBsAg secretion inhibition is still unknown [4,42]. For this, we performed docking on known cellular factors involved in HBsAg and HBV particle secretion including CypA, Annexin II and Rab7 [10,13,26].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the triazole derivates of this compound have similar anti-HBV effects [38,39]. Anti-HBV potential of this non-toxic compound are hypothesized to be result of HBsAg inhibition through direct interaction with the viral or host molecules [4,38,42]. Cyclophilin A (CypA), Annexin II, and Ras-Associated Protein 7 (Rab7) are known cellular components involved in HBsAg secretion (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Prediction of HBF-0259 interactions with hepatitis B Virus receptors and surface antigen secretory factors

Mohebbi¹,

Mohammadi

Memarian

2016

VirusDis.

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Hepatitis B virus (HBV) is an etiological agent of viral hepatitis, which may lead to cirrhosis, and hepatocellular carcinoma. Current treatment strategies have not shown promising effect to date but various complications such as, drug toxicity-resistance have been reported. Study on newly discovered compounds, with minimal side effects, as specific HBV inhibitors is a fundamental subject introducing new biologic drugs. Here, we aimed to, by prediction, estimate interactions of HBF-0259 as a nontoxic anti-HBV compound on inhibiting the HBV through either interaction with the viral entry or HBsAg secreting factors using In Silico procedure. Molecular docking was performed by Hex 8.0.0 software to predict the interaction energy (Etot) between HBF-0259 and known cellular factors involved in HBV entry and HBsAg secreting factors. Hex 8.0.0 also employed to create protein-protein complexes. These interactions were then used to analyze the binding site of HBF-0259 within the assumed receptors by MGLTools software. Finally, the amino acid sequences involved in this interaction were aligned for any conservancy. Here, we showed that HBF-0259 Etot with CypA (-545.41 kcal/mol) and SCCA1 (499.68 kcal/mol), involved in HBsAg secretion and HBV integration, respectively, was higher than other interactions. Furthermore, HBF-0259 predicted interaction energy was even higher than those of CypA inhibitors. In addition, we claim that preS1 and/or preS2 regions within HBsAg are not suitable targets for HBF-0259. HBF-0259 has higher interaction energy with CypA and SCCA1, even more than other known receptors, co-receptors, viral ligands, and secretory factors. HBF-0259 could be introduced as potent anti-viral compound in which CypA and or SCCA1, as previously shown, are involved.

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Design, Synthesis, and Biological Evaluation of Triazolo-pyrimidine Derivatives as Novel Inhibitors of Hepatitis B Virus Surface Antigen (HBsAg) Secretion

Cited by 115 publications

References 36 publications

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

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

Prediction of HBF-0259 interactions with hepatitis B Virus receptors and surface antigen secretory factors

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