Capsid assembly mod 
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  • ||||||||||  Journal:  Resistance in marine cyanobacteria differs against specialist and generalist cyanophages. (Pubmed Central) -  Mar 24, 2020   
    We hypothesize that this is tolerated due to genome polyploidy, which we found for certain strains of both Synechococcus and Prochlorococcus Our findings unveil a heavy cost of promiscuous entry of generalist phages into nonhost cells that is rarely paid by specialist phages and suggests the presence of unknown mechanisms of intracellular resistance in the marine unicellular cyanobacteria. Furthermore, these findings indicate that the range for virus-mediated horizontal gene transfer extends beyond hosts to nonhost cyanobacterial cells.
  • ||||||||||  Journal:  Atomic structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes. (Pubmed Central) -  Mar 10, 2020   
    Incompatible distances revealed by the atomic structures rationalize the lack of CATC's binding to triplexes Ta, Tc, and Tf in HHV-6B. Our results offer insights into HHV-6B capsid assembly and the roles of its tegument proteins, including not only the β-herpesvirus-specific pU11 and pU14, but also those conserved across all subfamilies of Herpesviridae.
  • ||||||||||  Journal:  Thermostability of the Foot-and-Mouth Disease Virus Capsid Is Modulated by Lethal and Viability-Restoring Compensatory Amino Acid Substitutions. (Pubmed Central) -  Mar 3, 2020   
    The implications for the mechanism of genome uncoating in FMDV and the development of thermostabilized vaccines against foot-and-mouth disease are discussed.IMPORTANCE This study provides novel insights into the little known structural determinants of the balance between thermal stability and instability in the capsid of foot-and-mouth disease virus, and into the relationship between capsid stability and virus infectivity. The results provide new guidelines for the development of thermostabilized empty capsid-based recombinant vaccines against foot-and-mouth disease, one of the economically most important animal diseases worldwide.
  • ||||||||||  Journal:  Discovery of a New Sulfonamide Hepatitis B Capsid Assembly Modulator. (Pubmed Central) -  Feb 21, 2020   
    Herein, we report a novel series of HBV CAMs based on NVR 3-778, a potent CAM belonging to the SBA class. The lead compound (KR-26556) exhibited improved pharmacological activity and was examined through molecular docking studies.
  • ||||||||||  [VIRTUAL] HEPATITIS B VIRUS: NEW AGENTS ([VIRTUAL]) -  Feb 17, 2020 - Abstract #CROI2020CROI_96;    
    The targeting of the adaptive immune response may be particularly critical, since functional cure observed during spontaneous resolution of acute hepatitis B (sAg loss, sAb seroconversion) is heavily dependent on a brisk T cell response. In this regard, success using an anti-PD-1 approach has been observed in early studies of these agents in chronic hepatitis B. It is likely that some combination of these novel treatment approaches and existing approved agents will be necessary to achieve functional cure.
  • ||||||||||  Marvin Johnson Award: Targeted Therapeutic Delivery; Can the Dream Come True? (Freedom Ballroom E/F, Philadelphia 201 Hotel) -  Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_7987;    
    Such approaches can now be used for a variety of applications beyond therapeutic delivery. Finally, data from studies with cultured cells and mice will be used to illustrate VLP functionality and delivery performance.
  • ||||||||||  Engineering peptide insertions in virus-like particles using systematic apparent fitness landscapes (Freedom Ballroom E/F, Philadelphia 201 Hotel) -  Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_2620;    
    These effects dominate capsid assembly to such an extent that when these well-performing residues are grouped with extremely poorly performing residues, capsid assembly is still recovered. Ultimately, this work validates the utility of fitness landscapes in engineering VLPs, and illuminate how properties such as charge, flexibility, and the hydrogen bonding in the FG loop conserve capsid assembly, and expand the scope of peptide insertions which could be engineered into VLPs.
  • ||||||||||  Identification of a new class of HBV capsid assembly modulator (204B, Pennsylvania Convention Center) -  Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_1226;    
    NVR 3-778 is a first-in-class sulfonyl carboxamide-based HBV capsid assembly modulator (CAM) that has demonstrated proof of mechanism in a Phase I clinical trial. This presentation will describe the identification and hit to lead SAR of a completely novel series of pyrazolo piperidine HBV capsid assembly modulators.
  • ||||||||||  Journal:  Conservation and divergence of the I-domain inserted into the ubiquitous HK97 coat protein fold in the P22-like bacteriophages. (Pubmed Central) -  Jan 29, 2020   
    While the three I-domains share a six-stranded β-barrel skeleton, there are differences in (i) structure elements at the periphery of the conserved fold, (ii) the locations of disordered loops important in capsid assembly and conformational transitions, (iii) surfaces charges, and (iv) sequence motifs that are potential ligand-binding sites. These structural modifications on the rudimentary I-domain fold suggest considerable structural adaptability was needed to fulfill the versatile range of functional requirements for distinct phages.
  • ||||||||||  Preclinical, Journal:  Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus. (Pubmed Central) -  Jan 17, 2020   
    NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC values of 0.81 µM against HBV DNA and between 3.7 to 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achievable in mice and thus enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicted antiviral activity in vivo and supported further evaluation for safety, pharmacokinetics, and antiviral activity in HBV infected patients.
  • ||||||||||  Journal:  Atomic structure of the Epstein-Barr virus portal. (Pubmed Central) -  Jan 8, 2020   
    Here we present the atomic structure of the portal protein of Epstein-Barr virus, solved by cryo-electron microscopy at 3.5 Å resolution. The detailed architecture of this protein suggests that it plays a functional role in DNA retention during packaging.
  • ||||||||||  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.