- |||||||||| 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.
- |||||||||| Machine learning?guided evolution of AAV capsids and synthetic promoters to enable systemically delivered gene therapies for the brain () - Oct 15, 2023 - Abstract #ESGCT2023ESGCT_336;
Singleplex in vivo validation of the top promoters driving the expression of a progranulin (GRN) transgene yielded high quantities of GRN in cerebrospinal fluid and undetectable levels in serum, indicating greatly improved strength, specificity, and size profiles of the novel promoters compared to currently available options.Our high?throughput, ML?guided platforms not only enabled the identification of CNS?targeting capsids and promoters but by their nature represent body?wide models of capsid and promoter sequence features, facilitating rapid application to other tissue expression profiles. Combining specific and tunable promoters with novel tissue?specific AAV capsids will bridge the gap between targeted delivery and tailored expression, accelerating the development of safe and effective gene therapies across the body.
- |||||||||| 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: 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.
- |||||||||| JNJ-3989 / J&J, bersacapavir (JNJ-56136379) / J&J
P2b data, Journal: Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. (Pubmed Central) - Jul 14, 2023
P2b
Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. 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.
- |||||||||| 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.
- |||||||||| Journal: Structural Insights into the Assembly of the African Swine Fever Virus Inner Capsid. (Pubmed Central) - May 16, 2023
The structural studies of the ASFV inner capsid protein p150 performed in this research enable the building of a partial model of the icosahedral ASFV inner capsid, which provides a structural basis for understanding the structure and assembly of this complex virion. Furthermore, the structure of ASFV p150 represents a new type of fold for viral capsid assembly, which could be a common fold for the inner capsid assembly of nucleocytoplasmic large DNA viruses (NCLDV) and would facilitate the development of vaccine and antivirus drugs against these complex viruses.
- |||||||||| Zolgensma (onasemnogene abeparvovec-xioi) / Novartis, Roctavian (valoctocogene roxaparvovec) / BioMarin, Luxturna (voretigene neparvovec-rzyl) / Novartis, Roche
Development of Stabilized AAV Capsids for Vector Engineering (Concourse Hall 150 & 151) - May 3, 2023 - Abstract #ASGCT2023ASGCT_2094;
Adeno-associated virus (AAV) vectors are promising candidates for gene therapy, as illustrated by the recent FDA or EMA approvals of Luxturna, Zolgensma and Valoctocogene Roxaparvovec...To determine whether AAV9 capsids bearing a combination of these mutations had increased mutational tolerance, we generated peptide-modified capsid libraries within AAV9 or a highly stabilized capsid variant and screened these libraries for production fitness. This work informs the development of novel AAV capsids with increased mutational tolerance for AAV engineering.
- |||||||||| Modifying Immune Responses to Adeno-Associated Virus (AAV) Vectors by Capsid Engineering (Concourse Hall 152 & 153) - May 3, 2023 - Abstract #ASGCT2023ASGCT_2056;
Beyond that, humoral responses against AAV capsids measured by anti-AAV2 IgG2a antibodies were mitigated and delayed in AAV2.MB-injected mice independent of the route of administration. To conclude, by incorporating an immune-modulatory peptide into the AAV2 capsid we could modify the activation of innate as well as adaptive immunity in response to AAV2 vectors.
- |||||||||| ALG-000184 / Aligos Therap
Treatment for up to 24 weeks with the capsid assembly modulator ALG-000184 results in dose related reductions in HBsAg in subjects with HBeAg positive chronic hepatitis B (Poster Area) - Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_2076;
P1
Importantly, dosing with ALG-000184 plus ETV resulted in dose-dependent, clinically relevant declines in HBsAg, suggesting a potential role of ALG-000184 in combination regimens for functional cure. Figure: Table: Mean BL and change from BL in HBV DNA and HBsAg with ALG-000184 plus ETV or ETV alone HBV DNA HBsAg ALG-000184 100 mg + ETV ALG-000184 300 mg +ETV ETV ALG-000184 100 mg + ETV ALG-000184 300 mg +ETV ETV BL, mean (SEM) 8.6 (0.1) N=8 8.2 (0.3) N=11 8.1 (0.3) N=6 4.7 (0.1) N=8 4.4 (0.2) N=11 4.3 (0.1) N=6 CFB, mean (SEM) - 6.4 (0.2) Week 24 N=4 - 5.4 (0.3) Week 16 N=6 - 3.8 (0.3) Week 12 N=3 - 0.5 (0.1) Week 24 N=4 - 0.5 (0.2) Week 16 N=6 +0.05 (0.02) Week 12 N=3 BL= baseline.
- |||||||||| Journal: What will it take to cure hepatitis B? (Pubmed Central) - Mar 28, 2023
Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.
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