scholarly journals Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 770
Author(s):  
Sameera Senaweera ◽  
Haijuan Du ◽  
Huanchun Zhang ◽  
Karen A. Kirby ◽  
Philip R. Tedbury ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Small Molecule ◽  
Capsid Assembly ◽  
Single Digit ◽  
Protein Protein Interaction ◽  
Design And Synthesis ◽  
B Virus ◽  
Preclinical And Clinical Studies ◽  
Thermal Shift

Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts in identifying novel CpAM hits via a structure-based virtual screening against a small molecule protein-protein interaction (PPI) library, and pharmacophore-guided compound design and synthesis. Curated compounds were first assessed in a thermal shift assay (TSA), and the TSA hits were further evaluated in an antiviral assay. These efforts led to the discovery of two structurally distinct scaffolds, ZW-1841 and ZW-1847, as novel HBV CpAM hits, both inhibiting HBV in single-digit µM concentrations without cytotoxicity at 100 µM. In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.

scholarly journals Design and Synthesis of Small-molecule Hepatitis B Virus Capsid Self-assembly Inhibitors

2017 ◽  
Author(s):  
Anda Sīpola ◽  
Unda Dubova ◽  
Brigita Vīgante ◽  
Karīna Spunde ◽  
Tatjana Kozlovska ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Small Molecule ◽  
Self Assembly ◽  
Virus Capsid ◽  
Design And Synthesis ◽  
B Virus

scholarly journals A Small Molecule Inhibits and Misdirects Assembly of Hepatitis B Virus Capsids

2002 ◽  
Vol 76 (10) ◽  
pp. 4848-4854 ◽  
Author(s):  
Adam Zlotnick ◽  
Pablo Ceres ◽  
Sushmita Singh ◽  
Jennifer M. Johnson
Keyword(s):  
Hepatitis B Virus ◽  
Light Scattering ◽  
Binding Energy ◽  
Hepatitis B ◽  
Capsid Protein ◽  
Small Molecule ◽  
Size Exclusion ◽  
Capsid Assembly ◽  
B Virus

ABSTRACT Hepatitis B virus (HBV) capsids play an important role in viral nucleic acid metabolism and other elements of the virus life cycle. Misdirection of capsid assembly (leading to formation of aberrant particles) may be a powerful approach to interfere with virus production. HBV capsids can be assembled in vitro from the dimeric capsid protein. We show that a small molecule, bis-ANS, binds to capsid protein, inhibiting assembly of normal capsids and promoting assembly of noncapsid polymers. Using equilibrium dialysis to investigate binding of bis-ANS to free capsid protein, we found that only one bis-ANS molecule binds per capsid protein dimer, with an association energy of −28.0 ± 2.0 kJ/mol (−6.7 ± 0.5 kcal/mol). Bis-ANS inhibited in vitro capsid assembly induced by ionic strength as observed by light scattering and size exclusion chromatography. The binding energy of bis-ANS for capsid protein calculated from assembly inhibition data was −24.5 ± 0.9 kJ/mol (−5.9 ± 0.2 kcal/mol), essentially the same binding energy observed in studies of unassembled protein. These data indicate that capsid protein bound to bis-ANS did not participate in assembly; this mechanism of assembly inhibition is analogous to competitive or noncompetitive inhibition of enzymes. While assembly of normal capsids is inhibited, our data suggest that bis-ANS leads to formation of noncapsid polymers. Evidence of aberrant polymers was identified by light scattering and electron microscopy. We propose that bis-ANS acts as a molecular “wedge” that interferes with normal capsid protein geometry and capsid formation; such wedges may represent a new class of antiviral agent.

Small-Molecule Inhibitors for the Treatment of Hepatitis B Virus Documented in Patents

2013 ◽  
Vol 999 (999) ◽  
pp. 1-7
Author(s):  
Chang-An Geng ◽  
Li-Jun Wang ◽  
Rui-Hua Guo ◽  
Ji-Jun Chen
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
B Virus

scholarly journals Functional association of cellular microtubules with viral capsid assembly supports efficient hepatitis B virus replication

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Masashi Iwamoto ◽  
Dawei Cai ◽  
Masaya Sugiyama ◽  
Ryosuke Suzuki ◽  
Hideki Aizaki ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Virus Replication ◽  
Viral Capsid ◽  
Capsid Assembly ◽  
Functional Association ◽  
B Virus

scholarly journals A Kinase Chaperones Hepatitis B Virus Capsid Assembly and Captures Capsid Dynamics in vitro

2011 ◽  
Vol 7 (11) ◽  
pp. e1002388 ◽  
Author(s):  
Chao Chen ◽  
Joseph Che-Yen Wang ◽  
Adam Zlotnick
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Capsid Assembly ◽  
Virus Capsid ◽  
B Virus

Safety, tolerability, and pharmacokinetics of the novel hepatitis B virus capsid assembly modulator GST-HG141 in healthy Chinese subjects: a first-in-human single- and multiple-dose escalation trial

2021 ◽  
Author(s):  
Cuiyun Li ◽  
Min Wu ◽  
Hong Zhang ◽  
Jiajia Mai ◽  
Lizhi Yang ◽  
...  
Keyword(s):  
Steady State ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Maximum Plasma ◽  
Capsid Assembly ◽  
Virus Capsid ◽  
B Virus ◽  
The Mean ◽  
Healthy Chinese ◽  
Chinese Subjects

Background: Hepatitis B virus capsid assembly modulators (HBV CAMs) are promising, clinically validated therapeutic agents for the treatment of chronic hepatitis B (CHB). The safety, tolerability, and pharmacokinetic (PK) profiles of GST-HG141, a novel HBV CAM, were evaluated in healthy Chinese volunteers. Method: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (50, 100, 200, 300, 400, or 500 mg) study comprising a food-effect investigation (300 mg), and a multiple-ascending-dose (MAD) (100 or 200 mg BID) study. Result: GST-HG141 reached the maximum plasma concentration (C max ) at 1.25–3.00 h (median T max ). The exposure exhibited a linear increase, while the mean half-life (t 1/2 ) ranged from 13.096 h to 22.121 h. The exposure of GST-HG141 (300 mg) was higher after food intake by about 2.4-fold. In the MAD study, steady-state was reached at around day 5, and the mean trough steady-state concentrations were 423 and 588 ng/mL for 50 and 100mg cohorts, respectively. The ratios of GST-HG141 accumulation were <1.5. GST-HG141 was well tolerated in healthy Chinese subjects. The rates of adverse events (AEs) in the GST-HG141 cohort did not differ from those of the placebo cohort. Conclusion: GST-HG141 was tolerated in healthy Chinese subjects. The safety and PK profiles of GST-HG141 support the further evaluation of its efficacy in individuals with CHB.

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

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Franck Amblard ◽  
Sebastien Boucle ◽  
Leda Bassit ◽  
Bryan Cox ◽  
Ozkan Sari ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nucleoside Analogs ◽  
Humanized Mouse Model ◽  
Single Digit ◽  
Viral Loads ◽  
Antiviral Responses ◽  
B Virus

ABSTRACT 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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