- |||||||||| [VIRTUAL] Revealing the mechanisms of viral capsid assembly using computational approaches (Room: Zoom Room 09) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_7189;
Formulas generated for the total number of each binding mode within one capsid show the mode within trisymmetron are dominating the stabilization of the capsid which is consistent to previous observation. Besides the viral capsid assembly, methods introduced in this study can be applied to study more complicated assembly process for other biomolecular structures.
- |||||||||| [VIRTUAL] HPV virus-like particle formation conserves key structural elements to ensure assembly across types (Room: Virtual Room) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_3372;
These conserved structures play an important role in enabling both capsid assembly as well as drive the formation of inter-capsomere disulfide bonds that provide long-term stability for the capsid. Finally, we analyze Cryo-EM structures of other types and demonstrate high conservation of these important 3D structural motifs across structures, even where sequence conservation is not maintained, suggesting synthetic targets that could promote the high-fidelity assembly of VLPs across types.
- |||||||||| Approaches for mining natural products databases for ribonucleocapsid assembly inhibitors (Room: Hall B4) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_2277;
In the initial studies, we report that the highest-ranking compounds bind to the RNA binding site of N protein. This approach seems feasible for the identification of lead compounds in the discovery of inhibitors that target a crucial step in the life cycle of zoonotic RNA viruses.
- |||||||||| Preclinical, Journal: Capsid assembly is regulated by amino acid residues asparagine 47 and 48 in the VP2 protein of porcine parvovirus. (Pubmed Central) - Aug 7, 2021
Site-directed mutation at 48Asn did not affect the ability of monomers to form into oligomers, but destroyed the ability of oligomers to assemble into macromolecular particles, influencing both capsid assembly and HA activity. Our findings provide valuable information on the mechanisms of PPV capsid assembly and the possibility of chimeric VLP vaccine development by replacing the first 47 amino acids at the N-terminal of the VP2 protein.
- |||||||||| Journal: Dynamics of the SARS-CoV-2 nucleoprotein N-terminal domain triggers RNA duplex destabilization. (Pubmed Central) - Jul 28, 2021
Based on experimental information available in the literature, we constructed kinetics models for N-NTD-mediated dsRNA melting. Our results support a 1:1 stoichiometry (N-NTD:dsRNA), matching MD simulations and raising different possibilities for N-NTD action: (i) two N-NTD arms of dimeric N would bind to two different RNA sites, either closely or spatially spaced in the viral genome, in a cooperative manner; (ii) monomeric N-NTD would be active, opening up the possibility of a regulatory dissociation event.
- |||||||||| Journal: Asymmetric reconstruction of mammalian reovirus reveals interactions among RNA, transcriptional factor µ2 and capsid proteins. (Pubmed Central) - Jul 23, 2021
Polymerase complexes in three Spinoreovirinae subfamily members are organized with different pseudo-D symmetries to engage their highly diversified genomes. The above interactions and those between symmetry-mismatched receptor-binding σ1 trimers and RNA-capping λ2 pentamers balance competing needs of capsid assembly, external protein removal, and allosteric triggering of endogenous RNA transcription, before, during and after infection, respectively.
- |||||||||| Review, Journal: Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B. (Pubmed Central) - Jul 14, 2021
This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."
- |||||||||| Journal: A lysine ring in HIV capsid pores coordinates IP6 to drive mature capsid assembly. (Pubmed Central) - Jun 24, 2021
Finally, in single molecule TIRF microscopy experiments, capsid lattices in permeabilised K25 mutant virions are rapidly lost and cannot be stabilised by IP6. These results suggest that the coordination of IP6 by a second charged ring in mature hexamers drives the assembly of conical capsids capable of reverse transcription and infection.
- |||||||||| Journal: Engineering a Virus-like Particle to Display Peptide Insertions Using an Apparent Fitness Landscape. (Pubmed Central) - Jun 22, 2021
This library generates a discrete map of three amino acid insertions permitted at this location, validates the FG loop as a valuable position for peptide insertion, and illuminates how properties such as charge, flexibility, and hydrogen bonding can interact to preserve or disrupt capsid assembly. Taken together, the results highlight the potential to engineer VLPs in a systematic manner, paving the way to exploring the applications of peptide insertions in biomedically relevant settings.
- |||||||||| tenofovir disoproxil fumarate / Generic mfg.
Journal: Discovery of Novel Pyrimidine-Based Capsid Assembly Modulators as Potent Anti-HBV Agents. (Pubmed Central) - Jun 22, 2021 One of the synthesized derivatives, compound 23h (R = MeSO, R = 1-piperidin-4-amine, R = 3-Cl-4-F-aniline) displayed potent inhibitory effects in the in vitro assays (52% inhibition in the protein-based assay at 100 nM and an IC value of 181 nM in the serum HBV DNA quantification assay). Moreover, treatment with compound 23h for 5 weeks significantly decreased serum levels of HBV DNA levels (3.35 log reduction) in a human liver-chimeric uPA/SCID mouse model, and these effects were significantly increased when 23h was combined with tenofovir, a nucleotide analogue inhibitor of reverse transcriptase used for the treatment of HBV infection.
- |||||||||| Review, Journal, IO biomarker: Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. (Pubmed Central) - Jun 22, 2021
Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
- |||||||||| Journal: Regulation of HBV Replication by Cyclin Docking Motifs in Core Protein. (Pubmed Central) - Jun 16, 2021
Mutations of these docking sites reduced capsid protein phosphorylation, impaired CDK2 packaging into HBV capsids, and blocked HBV infection. These results provide novel insights regarding CDK2 packaging into HBV capsids and the role of CDK2 in HBV infection and should facilitate the development of antiviral drugs that target the HBV capsid protein.
- |||||||||| Mavyret (glecaprevir/pibrentasvir) / AbbVie, Enanta Pharma
Clinical, Review, Journal: Breakthroughs and challenges in the management of pediatric viral hepatitis. (Pubmed Central) - Jun 8, 2021 Anti-HBV investigational compounds are reviewed in light of the pathophysiology in the pediatric population, including capsid assembly modulators, antigen secretion inhibitors, silencing RNAs, and immune modifiers. Recommendations for screening and management of immunosuppressed children or those with other risk factors or comorbidities are also summarized.
- |||||||||| Review, Journal: Structure, dynamics and phase separation of measles virus RNA replication machinery. (Pubmed Central) - Jun 4, 2021
Here, we review recent progress in this direction, covering the dynamics of the nucleocapsid assembly process, high resolution structure and dynamics of protein:RNA interactions, and the investigation of the role of intrinsic conformational disorder in pre-assembly nucleoprotein/phosphoprotein complexes. Finally, we discuss the role of viral factories in the form of phase-separated membraneless organelles formed by measles virus phospho and nucleoproteins that promote the assembly of nucleocapsid structures.
- |||||||||| Review, Journal: Recent Advances in Hepatitis B Treatment. (Pubmed Central) - Jun 3, 2021
Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.
- |||||||||| Journal: Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity. (Pubmed Central) - May 15, 2021
Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC > 10 µM) than NVR3-778 (CC, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.
- |||||||||| Journal: Dynamics of Hepatitis B virus capsid protein dimer regulate assembly through an allosteric network. (Pubmed Central) - May 7, 2021
The differences in dynamics when comparing HBV and human Cp149-Y132A as well as the differences in dynamics when comparing the HBV and WHV Cps allowed us to map an allosteric network within the HBV dimer. Through a careful comparison of structure, stability and dynamics using four different capsid protein dimers, we conclude that protein subunit dynamics regulate HBV capsid assembly.
- |||||||||| [VIRTUAL] Disorder in the C-terminus of VP Dictates AAP Requirement for AAV Capsid Assembly () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_288;
Conversely, VPs with reduced flexibility at the 2-fold or 5-fold axis do not autonomously oligomerize and are more prone to degradation, necessitating non-VP factors for promoting VP oligomerization via the 2-fold or 5-fold axis; and therefore, they are dependent on AAP for VP oligomerization and subsequent capsid assembly. Taken together, our data suggest that enhanced disorder in the C-terminus of VP that promotes structural flexibility in the 2-fold and 5-fold axis regions plays a critical role in conferring the ability to undergo AAP-independent capsid assembly.
- |||||||||| Journal: Berberine Chloride is an Alphavirus Inhibitor That Targets Nucleocapsid Assembly. (Pubmed Central) - Apr 10, 2021
BBC acted on a late step in the alphavirus exit pathway, namely the formation of the nucleocapsid containing the infectious viral RNA. Better understanding of nucleocapsid formation and its inhibition by BBC will provide important information on the mechanisms of infectious alphavirus production and may enable their future targeting in antiviral strategies.
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