Discovery of (1<i>H</i>-Pyrazolo[3,4-<i>c</i>]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

Wang, Chunting; Pei, Yukui; Wang, Lin; Li, Shuo; Jiang, Chao; Tan, Xu; Dong, Yunhui; Xiang, Ye; Ma, Yao; Liu, Gang

doi:10.1021/acs.jmedchem.0c00292

Cited by 22 publications

(14 citation statements)

References 51 publications

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“…In recent years, a few major chemical classes have been reported as novel capsid assembly modulators (CpAMs) ( Figure 1 ): heteroaryldihydropyrimidines (HAPs), phenylpropenamides (PPAs), sulfamoylbenzamides (SBAs), sulfamoylpyrroloamides (SPAs), and glyoxamoylpyrroloxamides (GLPs) [ 15 , 16 ]. Among them, HPAs, PPAs, and SBAs are the most studied [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

Senaweera

Zhang

et al. 2021

Viruses

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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.

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Section: Introductionmentioning

confidence: 99%

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

Senaweera

Zhang

et al. 2021

Viruses

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“…Cells were treated with indicated compounds for 6 days as previously described [28]. For secreted HBV DNA, HepAD38 and HepG2-HBV1.3 media were extracted via a boiling method according to the manufacturer's instructions (Kehua Bio-Engineering, Shanghai, China).…”

Section: Quantification Of Secreted and Intracellular Hbv Dnamentioning

confidence: 99%

“…Heteroaryldihydropyrimidines (HAPs) [20,21] and dibenzothiazepines (DBTs) [22] misdirect Cp dimers to assemble aberrant noncapsid structures. Phenylpropenamides (PPAs) [23], sulfamoylbenzamides (SBAs) [24], phthalazinones [25], sulfamoylpyrrolamides (SPAs) [26], glyoxamoylpyrroloxamides (GLPs) [27], and pyrazolopyridinylsulfonamides (PPSs) [28] induce Cp dimers to assemble empty, morphologically intact capsids devoid of pgRNA and DNA polymerase.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of N-Sulfonylpiperidine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication

Yang

Yin

et al. 2022

Viruses

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As a key element during HBV replication, a nucleocapsid is considered a promising target for the treatment of chronic hepatitis B. The present study aimed to identify small molecules as novel capsid assembly modulators with antiviral activity. Structure-based virtual screening of an integrated compound library led to the identification of several types of HBV inhibitors. Among these inhibitors, N-sulfonylpiperidine-3-carboxamides (SPCs) potently reduced the amount of secreted HBV DNA. Through structure–activity relationship studies, we identified an SPC derivative, namely, C-39, which exhibited the highest antiviral activity without causing cytotoxicity. Mechanism studies showed that C-39 dose-dependently inhibited the formation of HBV capsid, synthesis of cccDNA, e antigen (HBeAg), viral pregenomic RNA (pgRNA), and HBV DNA levels, thereby restraining HBV replication. In summary, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.

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“…Nucleoside analogues usually need to be taken for a long time to prevent disease rebound and are also prone to drug resistance. HBV surface antigen (HBsAg) can be detected in the serum of patients, the loss of which is considered as a functional cure [3] . Both of the above‐mentioned therapies can reduce the replication of HBV DNA, but offer a frustrating clinical cure as defined by detecting the presence of HBsAg in the serum.…”

Section: Introductionmentioning

confidence: 99%

“…HBV surface antigen (HBsAg) can be detected in the serum of patients, the loss of which is considered as a functional cure. [3] Both of the above-mentioned therapies can reduce the replication of HBV DNA, but offer a frustrating clinical cure as defined by detecting the presence of HBsAg in the serum. To improve the cure rate of HBV and avoid drug resistance, it is necessary to discover and develop novel therapeutic drugs with different mechanisms of action that have durable inhibitory effect on HBV replication.…”

Section: Introductionmentioning

confidence: 99%

Exploration of Novel Hepatitis B Virus Capsid Assembly Modulators by Integrated Molecular Simulations

et al. 2021

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Capsid protein (Cp) plays an important role in the entire life cycle of Hepatitis B Virus (HBV) and is considered as a novel anti-HBV target. A series of novel sulfamoylbenzamide (SBA) derivatives have been recently identified as HBV capsid assembly modulators (CAMs) with EC 50 values at a low micromolar range. In this study, ligand-and receptor-based molecular simulations were performed to understand the structureactivity relationships (SARs) and the interaction mechanisms of these novel HBV CAMs. The constructed three-dimensional quantitative SAR (3D-QSAR) models exhibited good predictive abilities and well explained the SARs of these novel CAMs. Docking results suggested that HBV Cp TRP102 and THR128 might be key residues, which could form significant hydrogen bonds with these CAMs. Molecular dynamics (MD) results indicated that the most potent CAM could stably bind to the HBV Cp dimer or hexamer rather than the monomer, indicating that the inter-dimer interface might be important for SBA CAMs to stably bind with HBV Cp. Furthermore, five novel hit compounds (N1-5) as HBV CAMs were screened out by a comprehensive virtual screening. Compounds N1 and N2 were proved to bind well with the HBV Cp dimer and hexamer by MD simulations, and might have stronger interactions with the protein than the most potent SBA. These results might provide advantageous enlightenments for designing and developing novel HBV CAMs.

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Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

Cited by 22 publications

References 51 publications

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

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

Structure-Based Discovery of N-Sulfonylpiperidine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication

Exploration of Novel Hepatitis B Virus Capsid Assembly Modulators by Integrated Molecular Simulations

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