Idée - Computational Biology - # Modulation of Hepatitis B Virus Core Protein Aggregation

Targeting Unconventional Binding Sites on the Hepatitis B Virus Core Protein to Induce Capsid Aggregation

Q: How could the peptide dimers be further optimized to enhance their potency and specificity for HBc?

To enhance the potency and specificity of the peptide dimers for HBc, several optimization strategies can be considered: Structure-Activity Relationship (SAR) Studies: Conducting SAR studies to understand the key structural elements of the peptide dimers that contribute to their binding affinity and efficacy. This can involve systematically modifying different parts of the peptide sequence to identify the optimal configuration for binding to HBc. Linker Optimization: The linker connecting the two peptide units in the dimer can be optimized to ensure proper spacing and orientation for simultaneous binding to multiple HBc sites. Adjusting the length, flexibility, and composition of the linker can enhance the overall binding affinity. Multivalency: Exploring the potential for multivalency by increasing the number of binding sites on the peptide dimer. By incorporating additional binding motifs or increasing the number of peptide units, the dimer can engage with more HBc molecules simultaneously, leading to enhanced aggregation. Cell-Penetrating Peptides (CPPs): Improving the delivery of the peptide dimers into cells by optimizing the CPP component. Enhancing the cell penetration efficiency of the CPP can ensure effective intracellular targeting of HBc for aggregation. Stability and Pharmacokinetics: Assessing the stability and pharmacokinetic properties of the peptide dimers to ensure adequate bioavailability and duration of action. Modifications to enhance stability against degradation and improve circulation time can increase the efficacy of the compounds. Selectivity: Investigating the selectivity of the peptide dimers for HBc to minimize off-target effects. This can involve screening against related proteins or structures to ensure specific binding to HBc without interfering with other cellular components.

Q: What are the potential limitations or off-target effects of using these HBc-aggregating compounds as antivirals in a clinical setting?

While HBc-aggregating compounds show promise as antivirals, there are potential limitations and off-target effects to consider: Cytotoxicity: The aggregation of HBc induced by the compounds may lead to cytotoxic effects in host cells. Excessive aggregation could disrupt normal cellular processes and cause cell damage or death. Immunogenicity: The introduction of foreign peptides into cells could trigger an immune response, leading to inflammation or immune-mediated reactions. This immune response may limit the effectiveness of the compounds or cause adverse effects. Resistance: Prolonged use of HBc-aggregating compounds could potentially lead to the development of resistance in HBV strains. The virus may evolve to evade the effects of the compounds, reducing their efficacy over time. Off-Target Effects: The compounds may interact with unintended targets in the cell, leading to off-target effects. This could result in disruptions to normal cellular functions or unintended consequences on other biological processes. Delivery Challenges: Ensuring efficient delivery of the compounds to the target cells and tissues in a clinical setting can be challenging. Achieving the right concentration at the site of action while minimizing systemic exposure is crucial for therapeutic success. Clinical Safety: Before clinical use, thorough safety assessments, including toxicity studies and pharmacokinetic evaluations, are essential to ensure the compounds are safe for human use and do not cause harm.

Concepts de base

Synthetic dimeric compounds targeting two distinct binding pockets on the hepatitis B virus core protein can induce capsid aggregation, providing an alternative strategy to disrupt the viral life cycle.

Résumé

The content explores two distinct binding pockets on the hepatitis B virus (HBV) core protein (HBc) as potential targets for developing new antivirals.

The first pocket is a hydrophobic pocket located at the center of HBc dimers. The authors synthesized a geranyl dimer that binds to this pocket with micromolar affinity. Cryo-electron microscopy confirmed the binding of geraniol to this pocket.

The second pocket is located at the tips of the capsid spikes. The authors designed dimeric peptides that bind to this pocket with nanomolar affinity, significantly higher than their monomeric counterparts. These peptide dimers were found to induce aggregation of HBc in vitro and in living cells expressing HBc.

The authors provide structural insights into the binding of these dimeric compounds to the HBc capsid. They demonstrate that the peptide dimers can cross-link neighboring HBc dimers or capsids, leading to aggregation. This aggregation effect resembles the capsid assembly modulation observed with classical HBc-targeting antivirals.

The findings highlight the potential of targeting these alternative binding pockets on the HBc as a strategy to disrupt the HBV life cycle, complementing existing approaches that target the canonical hydrophobic pocket at the HBc dimer-dimer interface.

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biorxiv.org

Stats

The geranyl dimer binds to the central hydrophobic pocket of HBc-dimers with a KD of 63 ± 8 μM.
The SLLGRM-dimer, P2-dimer, and P1-dimer bind to the spike tips of HBc with KDs of 4.9 ± 0.7 μM, 1.9 ± 0.4 μM, and 312 nM, respectively.
The P1-dimer induces turbidity of an HBc solution at a 1:10 ratio of P1-dimer to HBc, while the SLLGRM-dimer requires significantly higher concentrations to induce aggregation.

Citations

"The peptide dimers display low micromolar to nanomolar affinity to HBc, the affinity increases with the elongation of the binding sequence."
"P1dC induces HBc aggregates in living HEK293 cells, while the scrambled peptide does not."
"Cryo-EM confirms the binding of peptide dimers to the spike tips of HBc capsids and their capsid-aggregating properties."

Idées clés tirées de

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

by Khay... à www.biorxiv.org 05-01-2024

https://www.biorxiv.org/content/10.1101/2024.04.29.591677v1

Questions plus approfondies

How could the peptide dimers be further optimized to enhance their potency and specificity for HBc?

To enhance the potency and specificity of the peptide dimers for HBc, several optimization strategies can be considered:

Structure-Activity Relationship (SAR) Studies: Conducting SAR studies to understand the key structural elements of the peptide dimers that contribute to their binding affinity and efficacy. This can involve systematically modifying different parts of the peptide sequence to identify the optimal configuration for binding to HBc.

Linker Optimization: The linker connecting the two peptide units in the dimer can be optimized to ensure proper spacing and orientation for simultaneous binding to multiple HBc sites. Adjusting the length, flexibility, and composition of the linker can enhance the overall binding affinity.

Multivalency: Exploring the potential for multivalency by increasing the number of binding sites on the peptide dimer. By incorporating additional binding motifs or increasing the number of peptide units, the dimer can engage with more HBc molecules simultaneously, leading to enhanced aggregation.

Cell-Penetrating Peptides (CPPs): Improving the delivery of the peptide dimers into cells by optimizing the CPP component. Enhancing the cell penetration efficiency of the CPP can ensure effective intracellular targeting of HBc for aggregation.

Stability and Pharmacokinetics: Assessing the stability and pharmacokinetic properties of the peptide dimers to ensure adequate bioavailability and duration of action. Modifications to enhance stability against degradation and improve circulation time can increase the efficacy of the compounds.

Selectivity: Investigating the selectivity of the peptide dimers for HBc to minimize off-target effects. This can involve screening against related proteins or structures to ensure specific binding to HBc without interfering with other cellular components.

What are the potential limitations or off-target effects of using these HBc-aggregating compounds as antivirals in a clinical setting?

While HBc-aggregating compounds show promise as antivirals, there are potential limitations and off-target effects to consider:

Cytotoxicity: The aggregation of HBc induced by the compounds may lead to cytotoxic effects in host cells. Excessive aggregation could disrupt normal cellular processes and cause cell damage or death.

Immunogenicity: The introduction of foreign peptides into cells could trigger an immune response, leading to inflammation or immune-mediated reactions. This immune response may limit the effectiveness of the compounds or cause adverse effects.

Resistance: Prolonged use of HBc-aggregating compounds could potentially lead to the development of resistance in HBV strains. The virus may evolve to evade the effects of the compounds, reducing their efficacy over time.

Off-Target Effects: The compounds may interact with unintended targets in the cell, leading to off-target effects. This could result in disruptions to normal cellular functions or unintended consequences on other biological processes.

Delivery Challenges: Ensuring efficient delivery of the compounds to the target cells and tissues in a clinical setting can be challenging. Achieving the right concentration at the site of action while minimizing systemic exposure is crucial for therapeutic success.

Clinical Safety: Before clinical use, thorough safety assessments, including toxicity studies and pharmacokinetic evaluations, are essential to ensure the compounds are safe for human use and do not cause harm.

Could the insights gained from targeting these alternative binding pockets on HBc be applied to develop novel antiviral strategies for other viral capsid proteins?

The insights gained from targeting alternative binding pockets on HBc could indeed be applied to develop novel antiviral strategies for other viral capsid proteins. Here are some ways in which these insights could be leveraged:

Structural Similarities: Many viral capsid proteins share structural similarities with HBc, including the presence of binding pockets and interaction sites. By studying the binding interactions of peptide dimers with HBc, similar strategies could be applied to target corresponding sites on other viral capsids.

Multivalent Binding: The concept of multivalent binding, as demonstrated by the peptide dimers targeting HBc, can be extended to other viral capsid proteins. Designing multivalent compounds that can simultaneously engage multiple binding sites on a viral capsid could enhance antiviral efficacy.

Linker Optimization: Optimizing the linker design between binding motifs in dimeric compounds can be applied to other viral capsid proteins. Tailoring the linker length and flexibility for specific capsid structures can improve the binding affinity and selectivity of antiviral agents.

Cell-Penetrating Strategies: Strategies for enhancing the intracellular delivery of antiviral compounds, such as using CPPs, can be adapted for targeting other viral capsids. Improving the cellular uptake and localization of antiviral agents can increase their effectiveness against a broader range of viruses.

Drug Development Paradigms: The development of novel antiviral strategies based on alternative binding pockets can inform drug discovery paradigms for other viral infections. By exploring diverse binding sites and mechanisms of action, researchers can uncover new avenues for combating viral diseases.

By applying the principles and findings from targeting alternative binding pockets on HBc to other viral capsid proteins, researchers can expand the repertoire of antiviral strategies and potentially develop innovative treatments for a variety of viral infections.