- |||||||||| morphothiadine mesilate (GLS4) / HEC Pharm
Journal: Discovery and mechanism verification of first-in-class hydrophobic tagging-based degraders of HBV core protein. (Pubmed Central) - Jun 9, 2025
Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.
- |||||||||| Journal: The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid. (Pubmed Central) - Jun 6, 2025
Comparative analysis of several central pore mutants lacking the R18 ring revealed that particle infectivity was not correlated with IP6 binding or capsid assembly, but rather with capsid stability and key post-entry events including reverse transcription and nuclear entry. Our results indicate that the central pore plays critical roles in both the assembly of capsids and their sustained stability post-entry.
- |||||||||| 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) - May 29, 2025
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. Finally, we demonstrate analytically and numerically that the relative change of HBV RNA more accurately reflects the antiviral effectiveness of a CAM than the relative change in HBV DNA.
- |||||||||| Review, Journal: How HIV-1 Uses the Metabolite Inositol Hexakisphosphate to Build Its Capsid. (Pubmed Central) - May 28, 2025
Indeed, such is the dependence of HIV-1 on IP6 that the virus actively packages it into virions during production. These discoveries have stimulated work from multiple labs into the role and importance of IP6 in HIV-1 replication, and is the subject of this review.
- |||||||||| Journal: Unraveling the Role of Mutations Outside the Basal Promoter and Precore Regions in the HBeAg-Negative Stage of Chronic Hepatitis B. (Pubmed Central) - May 22, 2025
Infectious clones generated from these genomes, each carrying between 21 and 66 amino acid substitutions, were characterized, showing that mutations in this stage differentially affected viral fitness in vitro by up- or downregulating HBV-DNA levels (ranging from 0.2 to 5 times those of the wild-type isolate), modulating capsid assembly, and altering the expression, secretion, and subcellular localization of viral proteins. In conclusion, while mutations in the BCP and precore regions are the primary drivers of HBeAg seroconversion, mutations outside these regions significantly influence HBV biology and potentially contribute to viral pathogenicity, underscoring the complex interplay between host and virus during the HBeAg-negative stage of chronic infection.
- |||||||||| Review, Journal: Mysteries of adenovirus packaging. (Pubmed Central) - May 20, 2025
We anticipate that lessons learned from adenovirus packaging will be highly valuable for the advancement of viral vectors and gene-delivery technologies. In reviewing this topic, we hope to stimulate discussion and facilitate future investigation that will ultimately resolve gaps in knowledge and expand our understanding of DNA virus genome packaging.
- |||||||||| Review, Journal: Hepatitis B Virus Nucleocapsid Assembly. (Pubmed Central) - May 3, 2025
It also highlights the contribution of cellular and cell-free systems to these discoveries and underscores the need for new approaches that reconstitute the complete HBV nucleocapsid assembly process. With the growing interest in developing nucleocapsid assembly inhibitors, some of which are currently in clinical trials, targeting Pol-pgRNA interactions and nucleocapsid assembly represents a promising therapeutic strategy for curing chronic hepatitis B.
- |||||||||| Review, Journal: Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease. (Pubmed Central) - Apr 27, 2025
We demonstrate applications of these principles in understanding viral evolution, drug resistance, and capsid assembly dynamics. Understanding dynamic allostery provides critical insights into protein evolution and offers new avenues for therapeutic interventions targeting allosteric regulation.
- |||||||||| Review, Journal: Structural studies of Parvoviridae capsid assembly and evolution: implications for novel AAV vector design. (Pubmed Central) - Apr 17, 2025
Along with the structure and evolution of the Parvoviridae capsids, computational methods have provided significant insights into the design of novel AAV vector techniques, which include (a) Structure-guided design of AAV capsids with improved properties, (b) Directed Evolution of AAV capsids for specific applications, and (c) Computational prediction of AAV capsid-receptor interactions. Further discussion addressed the ongoing challenges in the AAV vector design and proposed future directions for exploring enhanced computational tools, such as artificial intelligence/machine learning and deep learning.
- |||||||||| Journal: Research Status and Applications of Adeno-Associated Virus. (Pubmed Central) - Apr 16, 2025
Additionally, it examines the utilization of recombinant adeno-associated viruses (rAAV), detailing their production methods, mechanisms of cell entry and trafficking, and various serotypes. The review further interprets the role of rAAV by analyzing its current applications in research and therapy.
- |||||||||| Addressing the Manufacturing Bottleneck in Gene Therapies Through AAV Production in Whole Nicotiana benthamiana Plants (Exhibit Theater) - Apr 10, 2025 - Abstract #ASGCT2025ASGCT_1704;
This method preserves the natural stoichiometry of AAV vectors, prevents toxicity from overexpression, and reduces recombination issues, resulting in more consistent vector production. Moreover, the split-Cap system potentially allows for the creation of hybrid AAV vectors by mixing and matching VP1, VP2, and VP3 proteins from various serotypes, which could improve tropism and immune evasion in future applications.
- |||||||||| Evolving Synthetic Membrane Associated Accessory Proteins (synMAAPs) for Enhanced AAV Vector Egress (New Orleans Theater A) - Apr 10, 2025 - Abstract #ASGCT2025ASGCT_1051;
In addition to dissecting the biology of AAV egress, we integrate these findings into engineered AAV vector production workflows, demonstrating the potential for improved secretion and streamlined manufacturing eliminating the need for cell lysis, reducing host cell contaminants and potentially enabling continuous perfusion systems. Disease Focus of Abstract:None
- |||||||||| Journal: Weighted Ensemble Simulations Reveal Novel Conformations and Modulator Effects in Hepatitis B Virus Capsid Assembly. (Pubmed Central) - Apr 1, 2025
Here we employ the Weighted Ensemble methodology to characterize the free-energy landscape of our earlier determined functionally relevant progress coordinates. It is shown that this approach provides conformations outside those sampled by standard MD, as well as an increased number of structures with correspondingly enlarged binding pockets conducive to ligand binding, illustrating the utility of Weighted Ensemble for computational drug development.
- |||||||||| bersacapavir (JNJ-56136379) / J&J
Journal: Computational Approaches to Predict Hepatitis B Virus Capsid Protein Mutations That Confer Resistance to Capsid Assembly Modulators. (Pubmed Central) - Mar 27, 2025
MM/GBSA correctly predicted the resistance and sensitivity of more than 50% Cp mutations to BAY41-4109 with the structures 5E0I-BC and 5WRE-FA, and to JNJ-56136379 with the 5E0I-FA structure. Our work indicates that only the capsid or CpY132A hexamer structure bound with a CAM with similar chemical scaffold can be used for more accurately predicting the resistance and sensitivity of Cp mutations to a CAM molecule under investigation by molecular docking and/or MM/GBSA methods.
- |||||||||| Journal: Protein Carrier Adeno-Associated Virus. (Pubmed Central) - Mar 21, 2025
Importantly, this protein packaging capability can be translated to multiple AAV serotypes. Our work establishes AAV as a protein delivery vehicle, significantly expanding the utility of this viral vector for biomedical applications.
- |||||||||| Preclinical, Journal: Herpes simplex virus assembly and spread in murine skin after infection from the outside. (Pubmed Central) - Mar 18, 2025
Using advanced microscopy techniques, we tracked HSV-1 spread at the cellular level and intracellular assembly of all intermediate virus structures. This model offers a valuable tool for studying the initial stages of HSV-1 infection, assessing viral mutant phenotypes, and testing antiviral compounds in a more physiological context to provide critical insights into HSV-1 pathogenesis and therapeutic strategies.
- |||||||||| Journal: Structural basis for Ebola virus nucleocapsid assembly and function regulated by VP24. (Pubmed Central) - Mar 11, 2025
Mutational analysis identifies specific interactions between the two NPs and two VP24s and demonstrates that each of the two VP24s in different orientations distinctively regulates nucleocapsid assembly, viral RNA synthesis, intracellular transport of the nucleocapsid, and infectious virion production. Our findings highlight the sophisticated mechanisms underlying the assembly and functional regulation of the nucleocapsid and provide insights into antiviral development.
- |||||||||| Sunlenca (lenacapavir) / Gilead
Journal: The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir. (Pubmed Central) - Mar 10, 2025
Consequently, LEN treatment results in morphologically atypical virus particles containing malformed, hyper-stable CA assemblies, which fail to infect target cells. Moreover, we have uncovered an inverse correlation between inhibitor potency and CA levels in cell culture assays, which accounts for LEN's ability to potently (with picomolar EC50 values) inhibit HIV-1 maturation at clinically relevant drug concentrations.
- |||||||||| Journal: Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency. (Pubmed Central) - Feb 20, 2025
This work uncovers a structural mechanism by which HIV-1 adapts to a deficiency in IP6 packaging. Furthermore, the ability of G225R to promote mature capsid assembly in low-IP6 conditions provides a valuable tool for capsid-related studies and may indicate a heretofore unknown role for the unstructured C-terminus in HIV-1 capsid assembly.
- |||||||||| Journal: HBV polymerase recruits the phosphatase PP1 to dephosphorylate HBc-Ser170 to complete encapsidation. (Pubmed Central) - Feb 11, 2025
Therefore, HBV Pol may play a dual role by initially bringing pgRNA to phosphorylated HBc and recruiting PP1 for later completion of RNA packaging into the capsids. These findings not only decipher the mechanism by which Pol-mediated dephosphorylation of HBc regulates pgRNA encapsulation, but also reveal the possibility of PP1 as a potential target for antiviral development.
- |||||||||| Journal: Local Microenvironments of capsomer variants in the PBCV-1. (Pubmed Central) - Feb 3, 2025
Moreover, the identified salt bridges between Type V/I capsomers and their surrounding capsomers corroborate the results of electrostatic calculations, further highlighting the important residues involved in these interactions. Understanding these local capsid microenvironments will be essential to elucidate the mechanisms governing viral capsid assembly.
- |||||||||| Journal: Rabies virus phosphoprotein exhibits thermoresponsive phase separation with a lower critical solution temperature. (Pubmed Central) - Jan 12, 2025
Protein dimers assemble already below the saturation concentration, and condensation is driven by attractive conformation-specific interactions leading to reentrant liquid phase separation over a narrow range of salt concentration. We propose a minimal molecular model in which P can adopt three limit conformational states and the disordered N-terminal arms control the interactions between giant dipoles that is consistent with our observations.
- |||||||||| GST-HG141 / Fujian Cosunter
Clinical, P1 data, PK/PD data, Journal: Safety, pharmacokinetics, and antiviral efficacy of the novel capsid assembly modulator GST-HG141 in patients with chronic hepatitis B: a phase 1 trial with a randomized, placebo-controlled design. (Pubmed Central) - Dec 21, 2024
We propose a minimal molecular model in which P can adopt three limit conformational states and the disordered N-terminal arms control the interactions between giant dipoles that is consistent with our observations. These concentrations adequately covered the protein binding-adjusted EC50 (16.89 ng/mL) by factors of 4.4, 11.1, and 14.6 for doses of 25, 50, and 100
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