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  • ||||||||||  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.
  • ||||||||||  Journal:  Synthesis of the full-length hepatitis B virus core protein and its capsid formation. (Pubmed Central) -  Feb 15, 2024   
    Sequential ligations using four peptide segments enabled the synthesis of Cp183 via convergent and C-to-N direction approaches. After refolding under appropriate conditions, followed by the addition of nucleic acid, the synthetic Cp183 assembled into capsid-like particles.
  • ||||||||||  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) -  Feb 5, 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.
  • ||||||||||  Review, Journal:  Recent Advances in the Development of Sulfamoyl-Based Hepatitis B Virus Nucleocapsid Assembly Modulators. (Pubmed Central) -  Dec 27, 2023   
    Additionally, we explore newly identified sulfamoyl-based CAMs, including sulfamoyl bicyclic carboxamides, sulfamoyl aromatic heterocyclic carboxamides, sulfamoyl aliphatic heterocyclic carboxamides, cyclic sulfonamides, and non-carboxamide sulfomoyl-based CAMs. We believe that certain molecules derived from sulfamoyl groups have the potential to be developed into essential components of a well-suited combination therapy, ultimately yielding superior clinical efficacy outcomes in the future.
  • ||||||||||  Preclinical, Journal:  Novel non-HAP class A HBV capsid assembly modulators have distinct in vitro and in vivo profiles. (Pubmed Central) -  Dec 25, 2023   
    These so-called non-HAP CAM-As have intriguing properties in cell culture but also clear virus-infected cells from the mouse liver in a gradual and sustained way. We believe they represent a considerable improvement over previously reported molecules and may one day be part of curative treatment combinations for chronic hepatitis B.
  • ||||||||||  Journal:  Architecture of the baculovirus nucleocapsid revealed by cryo-EM. (Pubmed Central) -  Nov 23, 2023   
    In the base, these proteins interact with a 7-fold symmetric capsid plug, while a portal-like structure is seen in the central portion of head. Additionally, we propose an application of AlphaFold2 for model building in intermediate resolution density.
  • ||||||||||  lamivudine HBV / Generic mfg.
    Journal:  Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability. (Pubmed Central) -  Nov 17, 2023   
    The results from biological evaluation demonstrated that compound 6a-25 (EC = 0.020 ?M) exhibited greater potency than the positive drug lamivudine (EC = 0.09 ?M), and was comparable to the lead compound GLS4 (EC = 0.007 ?M)...Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 ?g mL; pH 7.0: 6.85 ?g mL; pH 7.4: 25.48 ?g mL), liver microsomal metabolic stability (t = 108.2 min), and lower hERG toxicity (10 ?M inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.
  • ||||||||||  Journal:  Molecular architecture of Salmonella typhimurium virus P22 genome ejection machinery. (Pubmed Central) -  Nov 12, 2023   
    Cryo-EM analysis of P22 mutants lacking the ejection proteins gp7 or gp20 and biochemical analysis of purified recombinant proteins suggest that gp7 and gp20 form a molecular complex associated with the tail apparatus via the portal protein barrel. We identified a putative signal transduction pathway from the tailspike to the tail needle, mediated by three flexible loops in the tail hub, that explains how lipopolysaccharide (LPS) is sufficient to trigger the ejection of the P22 DNA in vitro.
  • ||||||||||  Arc mediates a novel form of intercellular long-term depression (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_11344;    
    Arc that is transferred in EVs induces synaptic depression in neighboring dendrites. We propose that neurons incorporated into the memory "engram" that undergo LTP release Arc to increase the "signal-to-noise" of memory circuits by weakening synapses on neurons not active during memory encoding.
  • ||||||||||  Journal:  Impact of core protein naturally selected mutants associated with HBeAg-negative status in HBV biosynthesis. (Pubmed Central) -  Oct 30, 2023   
    Subsequently, the assessment of HBc mutants derived from HBeAg-negative patients in viral structure and replicative capacity revealed that HBc mutations have the ability to modulate the subcellular localization of the protein (either when the protein was expressed alone or in the context of viral replication), capsid assembly, and, depending on specific mutation patterns, alter covalently closed circular DNA (cccDNA) recycling and up- or downregulate viral replication. In conclusion, HBc mutations associated with HBeAg-negative status impact on various stages of the HBV life cycle modulating viral replication during the HBeAg-negative stage of infection.
  • ||||||||||  morphothiadine mesilate (GLS4) / HEC Pharm
    Journal:  Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators. (Pubmed Central) -  Oct 27, 2023   
    Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.
  • ||||||||||  ritonavir / Generic mfg.
    Journal:  Synthesis and evaluation of highly potent HBV capsid assembly modulators (CAMs). (Pubmed Central) -  Oct 24, 2023   
    1B) was performed and led to the discovery of non-toxic compound 10a displaying sub-nanomolar anti-HBV activity. Advanced toxicity and cellular pharmacology profiles of compounds 10a were also established and the results are discussed herein.
  • ||||||||||  bersacapavir (JNJ-56136379) / J&J
    Journal:  Binding characteristics of pyrrole-scaffold hepatitis B virus capsid inhibitors and identification of novel potent compounds. (Pubmed Central) -  Oct 9, 2023   
    This study used in silico computational modeling to provide insights into the binding characteristics between the HBV core protein and two pyrrole-scaffold inhibitors, JNJ-6379 and GLP-26, both in the CAM-Normal (CAM-N) series...Through analyses of the structure-activity and structure-druggability relations of a series of compounds, CU15 emerged as the most promising lead CAM-N compound, exhibiting sub-nanomolar potency and good pharmacokinetic profiles. Overall, the study demonstrated a practical approach to leverage computational methods for understanding key target binding features for rationale-based design, and for guiding the identification of novel compounds.
  • ||||||||||  Journal:  Single-molecule-binding studies of antivirals targeting the hepatitis C virus core protein. (Pubmed Central) -  Sep 29, 2023   
    Our work biochemically characterizes several of these binding interactions, highlighting both similarities and differences as well as strengths and weaknesses. These insights bolster the notion that this viral protein is a viable target for novel therapeutics and will help to guide future developments of these candidate antivirals.
  • ||||||||||  Review, Journal:  The role of nuclear pores and importins for herpes simplex virus infection. (Pubmed Central) -  Sep 18, 2023   
    Moreover, importin-? proteins exert antiviral effects by promoting the nuclear import of transcription factors inducing the expression of interferons (IFN), cytokines, and IFN-stimulated genes, and the IFN-inducible MxB restricts capsid docking to NPCs.
  • ||||||||||  Journal:  Modifying immune responses to adeno-associated virus vectors by capsid engineering. (Pubmed Central) -  Sep 11, 2023   
    Moreover, humoral responses against the capsid were mitigated as indicated by delayed IgG2a antibody formation and an increased NAb50. To conclude, insertion of the MyD88-derived peptide into the AAV2 capsid improved early steps of host-vector interaction and reduced innate and adaptive immune responses.
  • ||||||||||  Journal:  Molecular Dynamics Simulations of Deformable Viral Capsomers. (Pubmed Central) -  Aug 30, 2023   
    An assembly diagram in the space of capsomer-capsomer steric attraction and capsomer deformability reveals that assembling capsomers of higher deformability into capsids requires increasingly large steric attraction between capsomers. Increasing capsomer deformability can reverse incorrect capsomer-capsomer binding, facilitating transitions from malformed structures to symmetric capsids; however, making capsomers too soft inhibits assembly and yields fluid-like structures.
  • ||||||||||  Journal:  The autophagy machinery interacts with EBV capsids during viral envelope release. (Pubmed Central) -  Aug 28, 2023   
    However, BdRF1 was sufficient for the release of noninfectious viral envelopes as long as autophagy was not compromised. These data suggest that BVRF2 and BdRF1 are not only important for capsid assembly but together with the LC3B conjugation complex of ATG5-ATG12-ATG15L1 are also critical for EBV envelope release.
  • ||||||||||  Journal:  Relaxational dynamics of the T-number conversion of virus capsids. (Pubmed Central) -  Aug 27, 2023   
    However, it fails to provide a good representation of the time evolution of the state of assembly of the coat proteins in the very late stages of equilibration when one of the two species disappears from the solution. It appears that explicitly incorporating the nucleation barriers to assembly and disassembly is crucial for an accurate description of the experimental findings, at least under conditions where these barriers are sufficiently large.
  • ||||||||||  Journal:  Antiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus. (Pubmed Central) -  Aug 23, 2023   
    In addition, we built machine learning models to determine if they were able to predict the activity of this series of compounds. The novelty of these molecules indicated they were outside of the applicability domain of these models.
  • ||||||||||  Journal:  Cryo-EM structure of the nucleocapsid-like assembly of respiratory syncytial virus. (Pubmed Central) -  Aug 22, 2023   
    However, the molecular details of RSV nucleocapsid assembly remain unknown, which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle. Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.
  • ||||||||||  Journal:  Geometric approach to nonequilibrium hasty shortcuts. (Pubmed Central) -  Aug 22, 2023   
    We also find that the Mpemba-effect-like shortcuts only constitute a small fraction of the diverse categories of hasty shortcuts. This theory is validated and illustrated numerically in the self-assembly model inspired by viral capsid assembly processes.
  • ||||||||||  Journal:  Structure-based Design of Novel Hepatitis B Virus Capsid Assembly Modulators. (Pubmed Central) -  Aug 21, 2023   
    Initial optimization of four weakly active screening hits was performed via focused library synthesis. Lead compound 42 and close analogues 56 and 57 exhibited in vitro potency in the sub- and micromolar range along with good physico-chemical properties and were further evaluated in molecular docking and mechanism of action studies.
  • ||||||||||  Journal:  Structural and Biophysical Analysis of Adeno-Associated Virus Serotype 2 Capsid Assembly Variants. (Pubmed Central) -  Jul 28, 2023   
    However, to date, there are limited data available on the importance of the capsid viral protein (VP) symmetry-related interactions required to assemble and maintain the stability of the AAV capsids and the infectivity of the AAV capsids. Characterizing the residue type and interactions at these symmetry-driven assembly interfaces of AAV2 has provided the foundation for understanding their role in AAV vectors (serotypes and engineered chimeras) and has determined the residues or regions of the capsid that can or cannot tolerate alterations.
  • ||||||||||  Review, Journal:  The Premise of Capsid Assembly Modulators Towards Eliminating HBV Persistence. (Pubmed Central) -  Jul 21, 2023   
    Mono- or combination therapy, including CAMs with other HBV drugs, may potentially eliminate hepatitis B infections. Nevertheless, more data on their potential effect on HBV elimination is needed, especially when used daily for 6-12?months.
  • ||||||||||  Journal:  Energetics and Kinetic Assembly Pathways of Hepatitis B Virus Capsids in the Presence of Antivirals. (Pubmed Central) -  Jul 12, 2023   
    However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies. The observed capsid morphologies were closely reproduced in coarse-grained simulations by varying the F
  • ||||||||||  Journal:  Epstein-Barr virus envelope glycoprotein 110 inhibits NF-?B activation by interacting with NF-?B subunit p65. (Pubmed Central) -  May 29, 2023   
    Alternatively, gp110 might not disturb the association of p65 with non-transactivational subunit p50, but we showed it restrains activational phosphorylation (at Ser536) and nuclear translocation of p65, which we also found to be executed by the C-terminal cytoplasmic region of gp110. Altogether, these data suggest that the surface protein gp110 may be a vital component for EBV to antagonize the host's innate immune response, which is also helpful for revealing the infectivity and pathogenesis of EBV.