- |||||||||| Journal: Phosphatidylinositol-3-phosphate mediates Arc capsid secretion through the multivesicular body pathway. (Pubmed Central) - Aug 23, 2024
These results suggest that unlike the HIV Gag, whose membrane targeting requires interaction with plasma-membrane-specific phosphatidyl inositol (4,5) bisphosphate (PI(4,5)P2), the assembly of Arc capsids is mediated by PI3P at endocytic membranes. Understanding Arc's secretion pathway helps gain insights into its role in intercellular cargo transfer and highlights the commonality and distinction of trafficking mechanisms between structurally resembled capsid proteins.
- |||||||||| vebicorvir (ABI-H0731) / Assembly Biosci
Journal: A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B. (Pubmed Central) - Jul 29, 2024 By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drug's dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection...We developed a multiscale model of the intracellular HBV lifecycle and extracellular dynamics using a time-since-infection structured partial differential equation. We fit the model to participant data from a recent phase I trial, performed a detailed parameter sensitivity analysis, identified key mechanisms driving viral response to first-generation CAM treatment, and demonstrated that HBV RNA is more sensitive than HBV DNA to changes in CAM efficacy, highlighting the potential role of HBV RNA as a biomarker for CAM effectiveness.
- |||||||||| Journal: Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability. (Pubmed Central) - Jul 22, 2024
Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.
- |||||||||| Review, Journal: Chemical approaches to probe and engineer AAV vectors. (Pubmed Central) - Jul 9, 2024
Unlike genetic strategies, which can be more disruptive to the delicate capsid assembly and packaging processes, "late-stage" chemical modification of the assembled capsid-whether at natural amino acid residues or site-specifically installed noncanonical amino acid residues-often enables a versatile approach to introducing new properties to the capsid. This review summarizes the significant recent progress in AAV capsid engineering strategies, with a particular focus on chemical modifications in advancing the next generation of AAV-based gene therapies.
- |||||||||| Journal: A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex. (Pubmed Central) - Jun 19, 2024
An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
- |||||||||| Journal: Stimulus-responsive assembly of nonviral nucleocapsids. (Pubmed Central) - Apr 28, 2024
Analyses by transmission and cryo-electron microscopy confirmed that the resulting assemblies are structurally identical to their RNA-containing counterparts produced in vivo. Enzymatically triggered cage formation broadens the range of RNA molecules that can be encapsulated by NC-4, provides unique opportunities to study the co-assembly of capsid and cargo, and could be useful for studying other nonviral and viral assemblies.
- |||||||||| Journal: Limits of economy and fidelity for programmable assembly of size-controlled triply periodic polyhedra. (Pubmed Central) - Apr 26, 2024
Off-target misassembly occurs via incorporation of a variant of disclination defects, generalized to the case of hyperbolic crystals. The possibility of these topological defects is a direct consequence of the very same symmetry principles that underlie the economical design, exposing a basic tradeoff between design economy and fidelity of programmable, size controlled assembly.
- |||||||||| Journal: Structural morphing in the viral portal vertex of bacteriophage lambda. (Pubmed Central) - Apr 25, 2024
Our research focused on examining the structures of the portal vertex in both its preliminary prohead state and the fully mature virion state of bacteriophage lambda. By analyzing these structures, we were able to understand how the portal protein undergoes conformational changes during maturation, the mechanism by which it prevents DNA from escaping, and the process of DNA spirally gliding.
- |||||||||| Journal: Biophysics-Guided Lead Discovery of HBV Capsid Assembly Modifiers. (Pubmed Central) - Apr 15, 2024
The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.
- |||||||||| Journal: Identification of clickable HIV-1 capsid-targeting probes for viral replication inhibition. (Pubmed Central) - Mar 27, 2024
One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell-based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV-1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV-1 replication.
- |||||||||| Review, Journal: Toward a Functional Cure for Hepatitis B. (Pubmed Central) - Mar 27, 2024
These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.
- |||||||||| Preclinical, Journal: Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation. (Pubmed Central) - Mar 20, 2024
To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure.IMPORTANCETreatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.
- |||||||||| HBV RNA () - Mar 5, 2024 - Abstract #APASL2024APASL_2986;
The value of HBV RNA to predict virological relapse after stopping nucleos(t)ide analog is controversial, but detectable HBV RNA is found to associate with an increased risk of hepatitis flare. With the development of new therapeutics for chronic hepatitis B, HBV RNA can be a biomarker for target engagement particularly for capsid assembly inhibitors.
- |||||||||| Journal: SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction. (Pubmed Central) - Feb 21, 2024
Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle.
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