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  • ||||||||||  Journal:  Completion of the AAV Structural Atlas: Serotype Capsid Structures Reveals Clade-Specific Features. (Pubmed Central) -  Feb 26, 2021   
    This structural characterization completes our three-dimensional library of the current AAV serotypes to provide an atlas of surface loop configurations compatible with capsid assembly and amenable for future vector engineering efforts. Derived vectors could improve gene delivery success with respect to specific tissue targeting, transduction efficiency, antigenicity or receptor retargeting.
  • ||||||||||  Journal:  The Minor Matrix Protein VP24 from Ebola Virus Lacks Direct Lipid-Binding Properties. (Pubmed Central) -  Feb 25, 2021   
    Confocal imaging and cellular membrane fractionation analyses in human cells suggested VP24 did not specifically localize at the plasma membrane inner leaflet. Overall, we provide evidence that EBOV VP24 is not a lipid-binding protein and its presence in the viral matrix layer is likely not dependent on direct lipid interactions.
  • ||||||||||  Journal:  UBE1a Suppresses Herpes Simplex Virus-1 Replication. (Pubmed Central) -  Feb 25, 2021   
    PYR-41 reduced the co-localization of UBE1a and ICP27. Thus, our findings provide insights into the mechanism of UBE1a in the cellular response to viral infection.
  • ||||||||||  Journal:  Design, synthesis and anti-HBV activity of NVR3-778 derivatives. (Pubmed Central) -  Feb 17, 2021   
    Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.
  • ||||||||||  Journal:  The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid. (Pubmed Central) -  Feb 17, 2021   
    Significantly, many of the predicted hotspot residues were found to be conserved in representative viruses from different genera, suggesting that the molecular determinants of capsid assembly are conserved across the family. The analysis presented here can be applied to any icosahedral structure and provides a platform for in vitro mutagenesis studies to further investigate the significance of these hotspots in critical stages of the virus life cycle with a view to identify potential targets for antiviral drug design.
  • ||||||||||  Review, Journal:  HSV-1 Cytoplasmic Envelopment and Egress. (Pubmed Central) -  Feb 17, 2021   
    This generates mature infectious HSV-1 particles that must then be sorted to the termini of sensory neurons, or to epithelial cell junctions, for spread to uninfected cells. The focus of this review is upon our current understanding of the viral and cellular molecular machinery that enables HSV-1 to travel within infected cells during egress and to manipulate cellular organelles to construct its envelope.
  • ||||||||||  Journal:  Minimalistic coarse-grained modeling of viral capsid assembly. (Pubmed Central) -  Jan 28, 2021   
    All these models are highly coarse-grained, as it is still not possible to access the long timescales of such processes with atomistic modeling. Very different particle-based models can result in the same overall behavior, showing that such processes are governed by the effective anisotropic interactions between protein building blocks.
  • ||||||||||  Journal:  Hierarchical Natural Move Monte Carlo Refines Flexible RNA Structures into Cryo-EM Densities. (Pubmed Central) -  Jan 26, 2021   
    After validating the method on a simulated density map of tRNA, we applied it to objectively obtain the model of the folding intermediate for the specificity domain of ribonuclease P from Bacillus subtilis and refine a flexible ribosomal RNA (rRNA) expansion segment from the Mycobacterium tuberculosis (Mtb) ribosome in different conformational states. Finally, we used HNMMC to model atomic details and flexibility for two distinct conformations of the complete genomic RNA (gRNA) inside MS2, a single-stranded RNA virus, revealing multiple pathways for its capsid assembly.
  • ||||||||||  Journal:  Rapid prediction of crucial hotspot interactions for icosahedral viral capsid self-assembly by energy landscape atlasing validated by mutagenesis. (Pubmed Central) -  Jan 23, 2021   
    Our study goes all the way from resource-light, multiscale computational predictions of crucial hotspot inter-atomic interactions to validation using data on site-directed mutagenesis' effect on capsid assembly. By reliably and rapidly narrowing down target interactions, (no more than 1.5 hours per interface on a laptop with Intel Core i5-2500K @ 3.2 Ghz CPU and 8GB of RAM) our predictions can inform and reduce time-consuming in-vitro and in-vivo experiments, or more computationally intensive in-silico analyses.
  • ||||||||||  Levovir (clevudine) / Bukwang Pharma, Eisai
    Journal:  Biogenesis and molecular characteristics of serum hepatitis B virus RNA. (Pubmed Central) -  Jan 8, 2021   
    In summary, serum HBV RNA is secreted in noninfectious virion-like particle as spliced and poly(A)-free pgRNA. Our study will shed light on the molecular biology of serum HBV RNA in HBV life cycle, and aid the development of serum HBV RNA as a novel biomarker for CHB diagnosis and treatment prognosis.
  • ||||||||||  Journal:  N-terminal VP1 Truncations Favor T = 1 Norovirus-Like Particles. (Pubmed Central) -  Jan 1, 2021   
    Understanding the underlying processes in capsid size variation will help to produce particles of a defined capsid size presenting antigens consistent with intact virions. Next to vaccine production itself, this would be immensely beneficial for bio-/nano-technological approaches using viral particles as carriers or triggers for immunological reactions.
  • ||||||||||  Journal:  Hepatitis B Virus Core Protein Domains Essential for Viral Capsid Assembly in a Cellular Context. (Pubmed Central) -  Dec 30, 2020   
    Deletion of either the third helix or of the 124-135 residues of HBc had a dramatic impact on the assembly of the HBV capsid, inducing the formation of mis-assembled oligomers and monomers, respectively. This study shows that our approach using fluorescent derivatives of HBc is an innovative method to investigate HBV capsid formation.
  • ||||||||||  Journal:  Structures of capsid and capsid-associated tegument complex inside the Epstein-Barr virus. (Pubmed Central) -  Dec 23, 2020   
    Plasticity reaches the greatest level at the capsid-tegument interfaces involving SCP and capsid-associated tegument complexes (CATC): SCPs crown pentons/hexons and mediate tegument protein binding, and CATCs bind and rotate all five periportal triplexes, but notably only about one peri-penton triplex. These results offer insights into the EBV capsid assembly and a mechanism for recruiting cell-regulating factors into the tegument compartment as 'cargoes', and should inform future anti-EBV strategies.
  • ||||||||||  lamivudine / Generic mfg.
    Journal:  Identification and characterization of a novel hepatitis B virus pregenomic RNA encapsidation inhibitor. (Pubmed Central) -  Dec 18, 2020   
    In conclusion, we identified a novel class of compounds specifically targeting the ε-Pol interaction and thereby preventing the encapsidation of pgRNAs into viral capsids. This promising new HBV inhibitor class potently inhibits HBV amplification with distinct characteristics from existing NAs and other drugs currently under development, promising to add value to existing therapies for CHB.
  • ||||||||||  Journal:  Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors. (Pubmed Central) -  Nov 26, 2020   
    Structure-activity relationship studies based on metabolic pathways of 4r led to the identification of a phthalazinone derivative 19f with appropriate anti-HBV potencies (IC = 0.014 ± 0.004 μM in vitro), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of 19f resulted in a 2.67 log reduction of the HBV DNA viral load during a 4-week treatment with 150 mg/kg dosing twice daily.
  • ||||||||||  Journal:  Atomic-resolution structure of HIV-1 capsid tubes by magic-angle spinning NMR. (Pubmed Central) -  Nov 14, 2020   
    The inherent curvature in the CA tubes is controlled by conformational variability of residues in the linker region and of dimer and trimer interfaces. The present structure reveals atomic-level detail in capsid architecture and provides important guidance for the design of novel capsid inhibitors.
  • ||||||||||  Journal:  Adeno-associated virus capsid protein expression in Escherichia coli and chemically defined capsid assembly. (Pubmed Central) -  Nov 12, 2020   
    VLPs developed without assembly-activating protein (AAP), but adding purified recombinant AAP to the refolding process increased capsid yield. Our findings offer a new route to understand AAV assembly biology and open a toolbox for AAV production strategies that might enable capsid display for vaccination and matching of capsids with cargoes at large scale and low cost.
  • ||||||||||  Review, Journal:  Advances in hepatitis B therapeutics. (Pubmed Central) -  Nov 1, 2020   
    Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss...Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731, ARO-HBV and REP-2139...The current goal is to achieve a 'functional cure', with sustained serum HBsAg after drug discontinuation. Ultimately, the goal of HBV therapy will be virus eradication, an achievement that would require the elimination of the cccDNA reservoir within infected hepatocytes.
  • ||||||||||  Journal:  The carboxyl terminus (CT) of the PCV2 capsid protein (Cap) is critical to VLP assembly, cell entry, and propagation. (Pubmed Central) -  Oct 24, 2020   
    Our findings, therefore, suggest that the CT should be considered as one of the key epitopes, recognized by neutralizing antibodies, for vaccine design and a target for drug development to prevent PCV2-associated diseases (PCVAD). Furthermore, it is important to respect the function of K for its role in cell entry if employing either PCV2 VLPs for nanoscale DNA/drug cell delivery or the use of PCV2 VLPs to display a variety of foreign epitopes for immunization.
  • ||||||||||  Journal:  Role of the C-terminal cysteines in virus-like particle formation and oligomerization of the hepatitis E virus ORF2 truncated proteins. (Pubmed Central) -  Oct 21, 2020   
    Herein, by analyzing a set of ORF2 truncated proteins expressed in Escherichia coli, we found that the highly conserved C-terminal cysteines play a crucial role in the oligomerization of the truncated ORF2 proteins and in their assembly into VLPs, through the formation of dimer-dimer disulfide bonds; and the treatment of native HEV particles with dithiothreitol (DTT) induced the disassembly of the viral capsid, suggesting that the disulfide bonding is required for stabilizing the native HEV capsid. The present study sheds light on the structural role of the C-terminal region of the HEV capsid protein and contributes to the full understating of the viral capsid assembly process.
  • ||||||||||  Journal:  SR/RS Motifs as Critical Determinants of Coronavirus Life Cycle. (Pubmed Central) -  Sep 27, 2020   
    A precise and tight regulation of their function is achieved through phosphorylation of a number of serine residues within the SR/RS motifs by the Serine-Arginine protein kinases (SRPKs) that lead to delicate structural alterations. Given that coronavirus N proteins also contain SR/RS domains, we formulate the hypothesis that the viruses exploit the properties of these motifs to promote unpacking of viral RNA and virion assembly.
  • ||||||||||  Journal:  SAR studies in the sulfonyl carboxamide class of HBV capsid assembly modulators. (Pubmed Central) -  Sep 24, 2020   
    The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly process has shown clinical efficacy in early clinical trials. Herein is described the SAR exploration of NVR 3-778, the first clinical compound in the sulfonyl carboxamide class.
  • ||||||||||  Journal:  A Multiscale Model for the Self-assembly of Coat Proteins in Bateriophage MS2. (Pubmed Central) -  Sep 21, 2020   
    This is, to the best of our knowledge, the first multiscale model to simulate the assembling process of coat proteins in Bacteriophage MS2. The generality of this approach opens the door to its further applications in assembly of other viral capsids, virus-like particles and novel drug delivery systems.
  • ||||||||||  Review, Journal:  Geometric architecture of viruses. (Pubmed Central) -  Sep 16, 2020   
    Biologically significant defective capsids with or without nucleic acids are common in enveloped alpha-, flavi- and hepadnaviruses. The self-assembling, stable and non-infectious virus-like particles have been widely exploited as vaccine candidates and therapeutic molecules delivery vehicles.
  • ||||||||||  Prevymis (letermovir) / Merck (MSD), acyclovir / Generic mfg.
    Journal:  DNA Encapsidation and Capsid Assembly Are Underexploited Antiviral Targets for the Treatment of Herpesviruses. (Pubmed Central) -  Sep 11, 2020   
    Acyclovir is the drug of choice for HSV encephalopathy, yet there is an estimated 6-19% mortality rate with half of the survivors experiencing moderate to severe chronic neurological deficits...Drug resistance is a concern for HCMV, HSV, and VZV since approved drugs share common mechanisms of action. Targeting DNA encapsidation or capsid assembly provide additional options for the development of non-nucleoside, small molecule anti-herpesviral drugs.