Capsid assembly mod 
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  • ||||||||||  Journal:  Structural mass spectrometry goes viral. (Pubmed Central) -  Jan 1, 2020   
    Different MS approaches not only inform about size, stability, interactions and dynamics of virus assemblies, but also bridge the gap to other biophysical techniques, providing valuable constraints for integrative structural modeling of viral complex assemblies that are often inaccessible by single technique approaches. In this review, recent advances are highlighted, clearly showing that structural MS approaches in virology are moving towards systems biology and ever more experiments are performed on cellular level.
  • ||||||||||  Journal:  Kinetics of empty viral capsid assembly in a minimal model. (Pubmed Central) -  Dec 27, 2019   
    We find that the optimal conditions for an efficient assembly from a kinetic point of view strongly depart from the lowest capsid energy corresponding to the minimum of the potential energy landscape. Our work illustrates the important differences between the equilibrium and dynamic characteristics of viral self-assembly, and provides important insights on how to design specific interactions for a successful assembly of artificial viral cages.
  • ||||||||||  Journal:  Modular HIV-1 Capsid Assemblies Reveal Diverse Host-Capsid Recognition Mechanisms. (Pubmed Central) -  Dec 23, 2019   
    These assemblies reveal unique capsid-targeting mechanisms for each of the anti-HIV factors, TRIMCyp, MxB, and TRIM5α, linked to inhibition of virus uncoating and nuclear entry, as well as the HIV-1 cofactor FEZ1 that facilitates virus intracellular trafficking. This capsid assembly repertoire enables elucidation of capsid recognition modes by known capsid-interacting factors, identification of new capsid-interacting factors, and potentially, development of capsid-targeting therapeutics.
  • ||||||||||  Journal:  Molecular mechanisms of tetrahydropyrrolo[1,2-c]pyrimidines as HBV capsid assembly inhibitors. (Pubmed Central) -  Dec 21, 2019   
    The models established by three-dimensional quantitative structure-activity relationship could be used to predict the anti-HBV activities of the tetrahydropyrrolopyrimidines molecules. This study will help understanding the molecular mechanisms and novel designed small molecules could act as better inhibitors.
  • ||||||||||  Review, Journal:  Recent advances in the development of HBV capsid assembly modulators. (Pubmed Central) -  Dec 20, 2019   
    Capsid assembly modulators (CAMs) disrupt the encapsidation of pre-genomic RNA and can cause nucleocapsid disassembly, thereby affecting multiple steps of HBV replication and reduction of cccDNA pools. This review provides a concise overview of the development of CAMs and the progress achieved in understanding their interactions with HBV core proteins.
  • ||||||||||  Journal:  Involvement of a non-structural protein in poliovirus capsid assembly. (Pubmed Central) -  Nov 22, 2019   
    This study highlights a compensatory role of a non-structural regulatory protein, 2A, for an otherwise lethal mutation of the structural VP1 protein to facilitate increased thermal resistance. Studying how viruses respond to selection pressures is important for understanding mechanisms which underpin emergence of resistance and could be applied to the future development of antiviral agents and vaccines.
  • ||||||||||  Journal:  Bluetongue virus VP6 and genomic RNA interaction is essential for genome packaging. (Pubmed Central) -  Nov 22, 2019   
    We use multiple approaches including a robust RNA-protein finger-printing assay, which map the ssRNA binding sites of recombinant VP6 and the genomic dsRNA binding sites of the capsid-associated VP6. Together with virological and biochemical methods, within VP6, we for the first time identify the viral RNA packaging motif of a segmented dsRNA virus.
  • ||||||||||  Journal:  Residues on AAV Capsid Lumen Dictate Interactions and Compatibility With the Assembly-activating Protein. (Pubmed Central) -  Nov 21, 2019   
    Additionally, library-based approaches that simultaneously examine a large number of capsid variants would benefit from a universally functional AAP, which could hedge against overlooking variants with potentially valuable phenotypes but that were lost during vector library production due to incompatibility with the cognate AAP. Studying interactions between AAV's structural and nonstructural components enhances our fundamental knowledge of capsid assembly mechanisms and the protein-protein interactions required for productive assembly of the icosahedral capsid.
  • ||||||||||  GS-6207 / Gilead, rilpivirine LA (TMC278 LA) / J&J
    Preclinical, Journal:  A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. (Pubmed Central) -  Nov 14, 2019   
    GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.
  • ||||||||||  GS-6207 / Gilead
    Review, Journal:  HIV Capsid Inhibitors Beyond PF74. (Pubmed Central) -  Nov 3, 2019   
    Recently reported GS-CA inhibitors (GS-CA1 and GS-6207), have shown a strong potential and appear to contain a PF74 scaffold...A comparison of capsid structures in complex with host factors and PF74, reveals the presence of common chemical entities at topologically equivalent positions. Here we present the status of capsid inhibitors that contain PF74 scaffolds and propose that the PF74 scaffold may be used to develop strong and safe capsid inhibitors.
  • ||||||||||  Preclinical, Journal:  Novel non-heteroarylpyrimidine (HAP) capsid assembly modifiers have a different mode of action from HAPs in vitro. (Pubmed Central) -  Oct 9, 2019   
    Additionally, immunofluorescence staining of compound-treated HepAD38 cells showed that all non-HAP CAMs led to a shift in the equilibrium of HBV core antigen (HBcAg) towards complete cytoplasmic staining, while the HAP induced accumulation of HBcAg aggregates in the nucleus. Our study demonstrates that the novel scaffolds GPA, PT, and DBT exhibit class I modes of action, alike SBA and PPA, whereas HAP remains the only scaffold belonging to class II inhibitors.
  • ||||||||||  Journal:  Structures of Hepatitis B Virus Core- and e-Antigen Immune Complexes Suggest Multi-point Inhibition. (Pubmed Central) -  Sep 20, 2019   
    Here, by means of X-ray crystallography, analytical ultracentrifugation, and electron microscopy, we demonstrate that the antibodies have non-overlapping epitopes and effectively block biologically important assemblies of both proteins. These properties, together with the anticipated high tolerability and long half-lives of the antibodies, make them promising therapeutics.
  • ||||||||||  Review, Journal:  Packaging of Genomic RNA in Positive-Sense Single-Stranded RNA Viruses: A Complex Story. (Pubmed Central) -  Sep 20, 2019   
    In vitro and in vivo data show that there are different packaging mechanisms that control selective packaging of the genomic RNA during nucleocapsid assembly. The goals of this article are to explain some of the key experiments that support the contribution of these factors to packaging selectivity and to draw a general scenario that could help us move towards a better understanding of this step of the viral infectious cycle.
  • ||||||||||  Preclinical, Journal:  Hepatitis B virus DNA integration occurs early in the viral life cycle in aninfection model via NTCP-dependent uptake of enveloped virus particles. (Pubmed Central) -  Sep 11, 2019   
    ...HBV DNA integration was efficiently blocked by treatment with a 200 nM concentration of the HBV entry inhibitor Myrcludex B, but not with 10 μM tenofovir, 100 U of interferon alpha, or a 1 μM concentration of the capsid assembly inhibitor GLS4...Using this model, we show that integration already occurs when the infection is first established. Importantly, we provide here a system to analyze molecular factors involved in HBV integration, which can be used to develop strategies to halt its formation.
  • ||||||||||  Journal:  Dynamin is required for efficient cytomegalovirus maturation and envelopment. (Pubmed Central) -  Sep 1, 2019   
    Here we show that dynamin, which is an integral part of host endocytic machinery, is largely dispensable for early stages of CMV infection but is required at a late stage of CMV maturation. Studies on dynamin function in CMV infection will help us understand the host-virus interaction pathways amenable to targeting by conventional small molecules as well as by newer generation nucleotide-based therapeutics (e.g. siRNA, CRISPR/CAS gRNA, etc.).
  • ||||||||||  Journal:  Combining Cell-Free Protein Synthesis and NMR Into a Tool to Study Capsid Assembly Modulation. (Pubmed Central) -  Aug 24, 2019   
    We demonstrate that assembled capsids can be synthesized in amounts sufficient for structural studies, and show that addition of assembly modulators to the cell-free reaction produces objects similar to those obtained by addition of the compounds to preformed Cp183 capsids. These results establish the cell-free system as a tool for the study of capsid assembly modulation directly after synthesis by the ribosome, and they open the perspective of assessing the impact of natural or synthetic compounds, or even enzymes that perform post-translational modifications, on capsids structures.
  • ||||||||||  Journal:  A viral scaffolding protein triggers portal ring oligomerization and incorporation during procapsid assembly. (Pubmed Central) -  Jul 4, 2019   
    We report that preformed dodecameric rings of P22 portal protein, as opposed to portal monomers, incorporate into nascent procapsids, with preference for the procapsid portal conformation. Finally, a novel role for P22 scaffolding protein in triggering portal ring formation from portal monomers is elucidated and validated by incorporating de novo assembled portal rings into procapsids.
  • ||||||||||  Loprox gel/cream/shampoo/topical suspension (ciclopirox topical) / Bausch Health
    Preclinical, Journal:  Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly. (Pubmed Central) -  Jun 9, 2019   
    Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.
  • ||||||||||  Review, Journal:  Norovirus assembly and stability. (Pubmed Central) -  Jun 7, 2019   
    Gathering information on these differences and common features may deepen our understanding of norovirus emergence and can potentially be used to distinguish variants. However, more systematic studies and standardized approaches are required.
  • ||||||||||  Review, Journal:  A modelling paradigm for RNA virus assembly. (Pubmed Central) -  Jun 7, 2019   
    The model reveals how multiple sequence-structure motifs in the genomic RNA, termed packaging signals, with a shared coat protein recognition motif enable viruses to overcome a viral assembly-equivalent of Levinthal's Paradox in protein folding. The fitness advantages conferred by this mechanism suggest that it should be widespread in viruses, opening up new perspectives on viral evolution and anti-viral therapy.
  • ||||||||||  Journal:  Solid-state [C-N] NMR resonance assignment of hepatitis B virus core protein. (Pubmed Central) -  Jun 4, 2019   
    A secondary chemical shift analysis of the 140 visible residues suggests an overall alpha-helical three-dimensional fold matching that derived for Cp149 from the X-ray crystallography of the capsid, and from solution-state NMR of the Cp149 dimer. Interestingly, however, at three distinct regions the chemical shifts in solution differ significantly between core proteins in the capsid state versus in the dimer state, strongly suggesting the respective residues to be involved in capsid assembly.
  • ||||||||||  Journal:  Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. (Pubmed Central) -  May 7, 2019   
    The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.