Synthesis and Evaluation of <i>N</i>-Phenyl-3-sulfamoyl-benzamide Derivatives as Capsid Assembly Modulators Inhibiting Hepatitis B Virus (HBV)

Vandyck, Koen; Rombouts, Geert; Stoops, Bart; Tahri, Abdellah; Vos, Ann; Verschueren, Wim; Wu, Yingliang; Yang, Jingmei; Hou, Fuliang; Bing, Huang; Vergauwen, Karen; Dehertogh, Pascale; Berke, Jan-Martin; Raboisson, Pierre

doi:10.1021/acs.jmedchem.8b00654

Cited by 43 publications

(35 citation statements)

References 16 publications

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“…GLP-26 in combination with ETV potently decreased HBsAg and HBeAg levels in a humanized mouse model of infection, both during and, more importantly, after treatment. Previous studies have shown decreased HBV viral antigens during combination treatments (31), yet continued antiviral effects on these markers after treatment have not been yet reported for other CAMs from the same class, such as AB-423 (15) and JNJ-632 (32). The mechanisms resulting in the observed sustained response could arise from the very potent antiviral activity of GLP-26 (10 to 100 times more potent than AB-423 and JNJ-632) combined with a prolonged exposure from oral administration, leading to sustained efficacious levels of GLP-26.…”

Section: Discussionmentioning

confidence: 99%

Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

Amblard

Bouclé

Bassit

et al. 2020

Antimicrob Agents Chemother

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Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently closed circular DNA (cccDNA)—the viral minichromosome—in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment. Our group identified GLP-26, a novel glyoxamide derivative that alters HBV nucleocapsid assembly and prevents viral DNA replication. GLP-26 exhibited single-digit nanomolar anti-HBV activity, inhibition of HBV e antigen (HBeAg) secretion, and reduced cccDNA amplification, in addition to showing a promising preclinical profile. Strikingly, long term combination treatment with entecavir in a humanized mouse model induced a decrease in viral loads and viral antigens that was sustained for up to 12 weeks after treatment cessation.

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Section: Discussionmentioning

confidence: 99%

Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

Amblard

Bouclé

Bassit

et al. 2020

Antimicrob Agents Chemother

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“…82 However, similar compounds such as the 4,4-disubstituted-1,4-dihydropyrimidines 53a and 53b , developed by Janssen R&D Ireland, show weak anti-HBV activities using stable transfected cell lines HepG2.2.15 and HepG2.117 (IC 50 > 25 μ M). 83 …”

Section: Other Antiviral Agentsmentioning

confidence: 99%

Therapeutic Potential of Spirooxindoles as Antiviral Agents

et al. 2016

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Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiropyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure–activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.

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“…The disadvantages of nucleoside analogs prompted us and other researchers to invent and find new structural non-nucleoside analog compounds [ 11 , 12 , 13 , 14 , 15 , 16 ]. Many anti-HBV bioactive non-nucleoside analog compounds have been designed and developed on the basis of their interactions with receptor using molecular docking [ 17 , 18 , 19 , 20 , 21 ]. When HBV receptor binding domain PreS1 and PreS2 protein (including L protein, M protein and S protein) interact with small molecules, the virus will not allow entry to hepatocyte.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Bioactive Evaluation of Oxime Derivatives of Dehydrocholic Acid as Anti-Hepatitis B Virus Agents

et al. 2020

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Oxime derivatives of dehydrocholic acid and its esters were designed for anti-hepatitis B virus (HBV) drugs according to principles of assembling active chemical fragments. Twelve compounds were synthesized from dehydrocholic acid by esterification and oxime formation, and their anti-hepatitis B virus (HBV) activities were evaluated with HepG 2.2.15 cells. Results showed that 5 compounds exhibited more effective inhibition of HBeAg than positive control, among them 2b-3 and 2b-1 showed significant anti-HBV activities on inhibiting secretion of HBeAg (IC50 (2b-3) = 49.39 ± 12.78 μM, SI (2b-3) = 11.03; IC50 (2b-1) = 96.64 ± 28.99 μM, SI (2b-1) = 10.35) compared to the Entecavir (IC50 = 161.24 μM, SI = 3.72). Molecular docking studies showed that most of these compounds interacted with protein residues of heparan sulfate proteoglycan (HSPG) in host hepatocyte and bile acid receptor.

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Synthesis and Evaluation of N-Phenyl-3-sulfamoyl-benzamide Derivatives as Capsid Assembly Modulators Inhibiting Hepatitis B Virus (HBV)

Cited by 43 publications

References 16 publications

Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

Therapeutic Potential of Spirooxindoles as Antiviral Agents

Design, Synthesis and Bioactive Evaluation of Oxime Derivatives of Dehydrocholic Acid as Anti-Hepatitis B Virus Agents

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