Pharmacomodulation of a ligand targeting the HBV capsid hydrophobic pocket

Briday, Mathilde; Hallé, François; Lecoq, Lauriane; Radix, Sylvie; Martin, Juliette; Montserret, Roland; Dujardin, Marie; Fogeron, Marie‐Laure; Nassal, Michael; Meier, Beat H.; Lomberget, Thierry; Böckmann, Anja

doi:10.1039/d2sc02420a

“…By combining the multimerization approach and rational linker design, these effectors may be evolved to even more potent binders of the hydrophobic pocket, that may have a pharmacological effect on HBV. [48] (10) (7) Cryo EM resolved a second effector pocket situated at the tips of capsid spikes at the inner dimer interface of the HBc-dimers. Using our structural knowledge of the capsid, particularly the distances between the spikes, we designed peptide dimers with the ability to simultaneously bind to neighboring spikes on the same capsid or attach to two distinct capsids (Supplementary Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…By combining the multimerization approach and rational linker design, these effectors may be evolved to even more potent binders of the hydrophobic pocket, that may have a pharmacological effect on HBV. [48]…”

Section: Discussionmentioning

confidence: 99%

Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

Khayenko,

Makbul,

Schulte

et al. 2024

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The hepatitis B virus (HBV) infection is a major global health problem, with chronic infection leading to liver complications and high death toll. Current treatments, such as nucleos(t)ide analogs and interferon-α, effectively suppress viral replication but rarely cure the infection. To address this, new antivirals targeting different components of the HBV molecular machinery are being developed. Here we investigated the hepatitis B core protein (HBc) that forms the viral capsids and plays a vital role in the HBV life cycle. We explored two distinct binding pockets on the HBV capsid: the central hydrophobic pocket of HBc-dimers and the pocket at the tips of capsid spikes. We synthesized a geranyl dimer that binds to the central pocket with micromolar affinity, and dimeric peptides that bind the spike-tip pocket with nanomolar affinity. Cryo-electron microscopy further confirmed the binding of peptide dimers to the capsid spike tips and their capsid-aggregating properties. Finally, we show that the peptide dimers induce HBc aggregation in vitro and in living cells. Our findings highlight two tractable sites within the HBV capsid and provide an alternative strategy to affect HBV capsids.

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“…To elucidate the possible binding mode of (2R)-6 with the HBV core protein, molecular docking analysis was performed. [33][34][35] We carried out docking on the basis of the cocrystal structure of NVR-010-001-E2 and HBV capsid Y132A mutant protein (PDB code: 5E0I; Figure S1). [36] From the crystal structure consisting of six subunits and six native ligands, subunits B and C were prepared as receptor proteins.…”

Section: Rational Designmentioning

confidence: 99%

Discovery of 5‐alkyl‐2‐pyrazol‐oxazolidin‐4‐one derivatives as novel hepatitis B virus capsid assembly modulators

Guan

¹

,

Wang

²

,

Wang

³

et al. 2023

Archiv der Pharmazie

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The "magic methyl effect" strategy was used to design a series of 5-alkyl-2-pyrazoloxazolidin-4-one derivatives as novel hepatitis B virus (HBV) capsid assembly modulators. Most of these compounds exhibited potent HBV inhibitory activities with low cytotoxicities in HepG2.2.15 cells. The most promising compounds 9d and 10b had single-digit nanomolar IC 50 values with a high selectivity index. Compared with the lead compound (3.0%), they caused 15% and 18% decreases in HBe antigen secretion at 1.0 μM, respectively. In addition, compounds 9d and 10b possessed good pharmacokinetic profiles with oral bioavailability values of 56.1% and 48.9%, respectively. These results indicated that the two compounds were potential therapeutic agents for HBV infection.

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Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

Khayenko,

Makbul,

Schulte

et al. 2024

Preprint

0

View full text Add to dashboard Cite

The hepatitis B virus (HBV) infection is a major global health problem, with chronic infection leading to liver complications and high death toll. Current treatments, such as nucleos(t)ide analogs and interferon-α, effectively suppress viral replication but rarely cure the infection. To address this, new antivirals targeting different components of the HBV molecular machinery are being developed. Here we investigated the hepatitis B core protein (HBc) that forms the viral capsids and plays a vital role in the HBV life cycle. We explored two distinct binding pockets on the HBV capsid: the central hydrophobic pocket of HBc-dimers and the pocket at the tips of capsid spikes. We synthesized a geranyl dimer that binds to the central pocket with micromolar affinity, and dimeric peptides that bind the spike-tip pocket with nanomolar affinity. Cryo-electron microscopy further confirmed the binding of peptide dimers to the capsid spike tips and their capsid-aggregating properties. Finally, we show that the peptide dimers induce HBc aggregation in vitro and in living cells. Our findings highlight two tractable sites within the HBV capsid and provide an alternative strategy to affect HBV capsids.

show abstract

Pharmacomodulation of a ligand targeting the HBV capsid hydrophobic pocket

Abstract: Hepatitis B virus (HBV) is a small enveloped retrotranscribing DNA virus and an important human pathogen. Its capsid-forming core protein (Cp) features a hydrophobic pocket proposed to be central notably...

Cited by 4 publications

References 31 publications

Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

Discovery of 5‐alkyl‐2‐pyrazol‐oxazolidin‐4‐one derivatives as novel hepatitis B virus capsid assembly modulators

Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

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