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- | Journal: The Ebola Virus Interferon Antagonist VP24 Undergoes Active Nucleocytoplasmic Trafficking. (Pubmed Central) - Jan 29, 2022
Molecular mapping indicates that cytoplasmic localization of VP24 depends on a CRM1-dependent nuclear export sequence at the VP24 C-terminus. Nuclear export is not required for STAT1 antagonism, consistent with competitive karyopherin binding being the principal antagonistic mechanism, while export mediates return of nuclear VP24 to the cytoplasm where replication/nucleocapsid assembly occurs.
- | Journal: Hydrophobic Cargo Encapsulation into Virus Protein Cages by Self-Assembly in an Aprotic Organic Solvent. (Pubmed Central) - Jan 29, 2022
Assembly was found to be robust relative to a surprisingly broad range of DMSO concentrations. Cargos with poor initial stability in aqueous solutions were readily encapsulated at high DMSO concentrations and then transferred to aqueous solvents, where they remained stable and preserved their function for months.
- || Review, Journal: Motor Skills: Recruitment of Kinesins, Myosins and Dynein during Assembly and Egress of Alphaherpesviruses. (Pubmed Central) - Jan 28, 2022
To solve this challenging problem alphaherpesviruses, and their assembly intermediates, exploit microtubule- and actin-dependent cellular motors. This review focuses upon the mechanisms used by alphaherpesviruses to recruit kinesin, myosin and dynein motors during assembly and egress.
- Using computational approach to reveal the mechanisms of viral capsid assembly (Room 25B (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_12706;
This explains why the seam between two neighboring trisymmetrons becomes the breaking line when a giant virus capsid dissociates. Besides the viral capsid assembly, methods introduced in this study can be applied to study more complicated assembly process for other biomolecular structures.Structures of Paramecium Bursaria Chlorella Virus 1 (PBCV-1) capsid and its capsomers.
- | Journal: Dual-axis Volta phase plate cryo-electron tomography of Ebola virus-like particles reveals actin-VP40 interactions. (Pubmed Central) - Jan 27, 2022
Our data reveal actin filaments within virus-like particles in close proximity to the viral VP40 scaffold, suggesting a direct interaction between VP40 and actin filaments. Dual-axis VPP cryo-ET provides more complete 3D information at high contrast and allows for better interpretation of macromolecule interactions and pleomorphic organizations.
- | Journal: Identification of (6S)-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamines as new HBV capsid assembly modulators. (Pubmed Central) - Jan 27, 2022
Chiral separation of 2f and 3k was conducted successfully, and (6S)-cyclopropyl DPPC isomers 2f-1, 2f-3, 3k-1 and 3k-3 were identified to be much more active than the corresponding (6R)-ones. The preliminary structure-activity relationship, particle gel assay and molecular modeling studies were also discussed, which provide useful indications for guiding the further rational design of new (6S)-cyclopropyl DPPC analogues.
- | Preclinical, Journal: Constant pH molecular dynamics of porcine circovirus 2 capsid protein reveals a mechanism for capsid assembly. (Pubmed Central) - Jan 11, 2022
Our findings provide the first atomic resolution mechanism of capsid assembly regulation. These findings are useful for the development of therapeutics that inhibit PCV2 self-assembly.
- | Journal: Oxadiazepinone HBV Capsid Assembly Modulators. (Pubmed Central) - Jan 8, 2022
Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
- | Journal, Tumor Mutational Burden: Ribonucleocapsid assembly/packaging signals in the genomes of the coronaviruses SARS-CoV and SARS-CoV-2: detection, comparison and implications for therapeutic targeting. (Pubmed Central) - Jan 6, 2022
These observations may be helpful in practical medical applications and are of basic interest. Communicated by Ramaswamy H. Sarma.
- | Preclinical, Journal: In vitro assembly and evaluation of Nora virus VLPs. (Pubmed Central) - Jan 6, 2022
Assemblies that contained VP4A and/or VP3 created VLPs with similar sizes to purified empty Nora virus capsids, potentially indicating that VP4A and/or VP3 are vital for Nora virus capsid structure, assembly, and/or stability. Not only does this study provide insight into the role of Nora virus proteins, but it may also lead to a deeper understanding of how Nora virus or other picorna-like viruses undergo assembly. Keywords: RNA viruses, Nora virus, picorna-like virus, virus-like particles, capsid assembly.
- | Journal: Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis. (Pubmed Central) - Jan 4, 2022
The results thus indicate that in addition to nucleocapsid assembly, interaction of Cp at dimer-dimer interface also plays important roles in the production and infectivity of progeny virions through modulation of nucleocapsid envelopment and uncoating. Similar interaction at reduced p17 dimer-dimer interface appears to be important for its metabolic stability and sensitivity to CpAM suppression of HBeAg secretion.
- | Journal: The KSHV ORF20 Protein Interacts with the Viral Processivity Factor ORF59 and Promotes Viral Reactivation. (Pubmed Central) - Jan 1, 2022
We investigated the role of the poorly characterized viral protein ORF20, and through proximity labeling, we found that ORF20 interacts with ORF59 in replication compartments and affects DNA replication and subsequent steps of the late viral life cycle. Collectively, these results provide insights into the possible contribution of ORF20 to the complex lytic DNA replication process and suggest that this highly conserved protein may be an important modulator of this key viral mechanism.
- | Journal: Kaposi's sarcoma-associated herpesvirus ORF17 plays a key role in capsid maturation. (Pubmed Central) - Dec 30, 2021
Furthermore, wild type KSHV produced a mature capsid, whereas ORF17-deficient and protease-dead KSHV produced a B-capsid, (i.e., a closed body possessing a circular inner structure). Therefore, ORF17 and its protease function are essential for appropriate capsid maturation.
- | Journal: Shape shifter: redirection of prolate phage capsid assembly by staphylococcal pathogenicity islands. (Pubmed Central) - Dec 29, 2021
We built atomic models for CP and Ccm, and show that Ccm occupies the pentameric capsomers in the isometric SaPIbov5 procapsids, suggesting that preferential incorporation of Ccm pentamers prevents the cylindrical midsection from forming. Our results highlight that pirate elements have evolved diverse mechanisms to suppress phage multiplication, including the acquisition of phage capsid protein homologs.
- || Review, Journal: Novel Therapies of Hepatitis B and D. (Pubmed Central) - Dec 27, 2021
Many of these new promising compounds such as entry inhibitors, covalently closed circular DNA (cccDNA) inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators and nucleic acid polymers are in various stages of clinical developments. In this review article, we provided a comprehensive overview of the structure and lifecycle of HBV, the limitations of the current therapies and a summary of the novel therapeutic agents for both HDV and HBV infection.
- | Journal: Identification and evaluation of antiviral potential of thymoquinone, a natural compound targeting Chikungunya virus capsid protein. (Pubmed Central) - Dec 25, 2021
Reduction in viral RNA copy number and viral replication as assessed by the qRT-PCR and immunofluorescence assay, confirmed the antiviral potential of TQ. Our study reveals that TQ is an effective antiviral targeting the hydrophobic pocket of CHIKV CP and may serve as the basis for development of a broad-spectrum therapy against alphaviral diseases.
- | Journal: The structure of a plant-specific partitivirus capsid reveals a unique coat protein domain architecture with an intrinsically disordered protrusion. (Pubmed Central) - Dec 23, 2021
We show that a disordered region at the apex of the protrusion is not required for capsid assembly and represents a hypervariable site unique to, and characteristic of, the plant-specific partitiviruses. These results suggest a structural basis for the acquisition of additional functions by partitivirus coat proteins that enables mutualistic relationships with diverse plant hosts.
- | Journal: Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer. (Pubmed Central) - Dec 23, 2021
Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases.
- | Preclinical, Journal: A novel method for the in vitro assembly of virus-like particles and multimeric proteins. (Pubmed Central) - Dec 16, 2021
Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases. The novel method presented here is simpler and faster than other reported methods for the assembly and disassembly of viral proteins, a step needed for most applications.
- | Journal: Identification of hepatitis B virus core protein residues critical for capsid assembly, pgRNA encapsidation and resistance to capsid assembly modulators. (Pubmed Central) - Dec 16, 2021
This later finding implies that encapsidation of viral DNA polymerase may depend on the interaction of Pol with a capsid assembly intermediate, but not free Cp dimers. Taking together, our findings reported herein shed new light on the mechanism of HBV nucleocapsid assembly and mode of CpAM action.
- | Journal: Probing the spatiotemporal patterns of HBV multiplication reveals novel features of its subcellular processes. (Pubmed Central) - Dec 1, 2021
In conclusion, these data provided spatially resolved molecular snapshots in the context of specific subcellular activities. The heterogeneity observed at single-cell level afforded valuable molecular insights which are otherwise unavailable from bulk measurements.
- | Vemlidy (tenofovir alafenamide) / Gilead
Journal: Generation of an HBV Core Phenotyping Assay for Evaluating HBV Capsid Compounds. (Pubmed Central) - Nov 29, 2021
Overall, 11 of 13 constructs replicated in vitro, 6 constructs showed reduced susceptibility to CAMs. The 11 polymorphs which could replicate in vitro remained sensitive to the nucleotide analog tenofovir alafenamide (TAF), indicating that there is no cross-resistance.
- | Journal: Development of a cellular high-content, immunofluorescent HBV core assay to identify novel capsid assembly modulators that induce the formation of aberrant HBV core structures. (Pubmed Central) - Nov 29, 2021
This compound displayed anti-HBV activity in HepG2.117 cells, providing proof-of-concept for our screening approach. We believe our combined biochemical and cellular high-content screening method will aid in expanding the range of CAM-A chemotypes.
- || Review, Journal: The Hepatitis B Virus Nucleocapsid-Dynamic Compartment for Infectious Virus Production and New Antiviral Target. (Pubmed Central) - Nov 29, 2021
Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.
- | Journal: Unravelling the involvement of cilevirus p32 protein in the viral transport. (Pubmed Central) - Nov 17, 2021
Furthermore, we report that MP possess the capacity to enter the nucleolus and to bind to a major nucleolar protein, the fibrillarin. Based on our findings, we provide a model for the role of the p32 in the intra- and intercellular viral spread.
- | Journal: SNAP47 Interacts with ATG14 to Promote VP1 Conjugation and CVB3 Propagation. (Pubmed Central) - Nov 17, 2021
Finally, we revealed that disulfide interactions had an important role in strengthening VP1 conjugation. Collectively, our study elucidated a mechanism by which SNAP47 and ATG14 promoted CVB3 propagation through facilitating viral capsid assembly.
- | Journal: Cheilitis Associated with a Novel Herpesvirus in Two Panther Chameleons (Furcifer pardalis). (Pubmed Central) - Nov 10, 2021
Based on the identical findings in both chameleons, we consider chamHV 1 to be a candidate aetiological agent of cheilitis in panther chameleons. This is the first report of skin lesions in a chameleon species associated with HV infection.
- | Journal: Autographa Californica Multiple Nucleopolyhedrovirus orf13 Is Required for Efficient Nuclear Egress of Nucleocapsids. (Pubmed Central) - Nov 4, 2021
Deletion of ac13 substantially impaired the egress of nucleocapsids from the nucleus to the cytoplasm, while the OB morphogenesis was unaffected. Taken together, our results indicated that ac13 was required for efficient nuclear egress of nucleocapsids during virion budding, but was dispensable for OB formation.
- ZM-H1505R / Zhimeng Biopharma
[VIRTUAL] SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF THE NOVEL HBV CAPSID ASSEMBLY INHIBITOR ZM-H1505R FOLLOWING MULTIPLE ASCENDING DOSES IN HEALTHY SUBJECTS (PART 2) () - Nov 2, 2021 - Abstract #AASLD2021AASLD_2409;
P1
Its plasma exposure was well above its effective inhibitory concentration and increased in a dose-proportional manner. The safety and PK profile of ZM-H1505R supports its further evaluation in CHB patients.
- JNJ-73763989 / J&J
[VIRTUAL] EFFICACY AND SAFETY OF THE siRNA JNJ-3989 AND/OR THE CAPSID ASSEMBLY MODULATOR (CAM) JNJ-6379 FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS INFECTION (CHB): RESULTS FROM THE PHASE 2B REEF-1 STUDY () - Nov 2, 2021 - Abstract #AASLD2021AASLD_2397;
JNJ-3989 showed a dose dependent response with up to 19.1% meeting the primary endpoint at Week 48 compared to 0% in the JNJ-6379 + NA and 2.2% in the PBO + NA arm. Reduction of HBsAg levels was greatest with JNJ-3989 200mg s.c. Q4W + NA.
- || Clinical, Journal: Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc. (Pubmed Central) - Oct 27, 2021
This domain-swapped structure resembles the dimeric protein C of flavivirus capsids, as well as the structure of histones dimers, domain-swapped transcription factors, and membrane-interacting BAK domains. The strong oligomerization properties of the isolated dArc lobe domains explain the ability of dArc to form capsids in the absence of any large N-terminal domain, in contrast to the mammalian protein.
- ALG-010133 / Aligos Therap
[VIRTUAL] TRIPLE COMBINATION OF ANTI-HEPATITIS B VIRUS DRUGS DEMONSTRATES SYNERGISTIC ACTIVITY IN VITRO () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1084;
Our HBV siRNA compound, ALG-125903, in combination with our ASO, ALG-020579 and STOPS molecule, ALG-010133, demonstrated synergistic activity in vitro . Further investigation of the strategy to combine HBV siRNA with ASO and STOPS compounds in human clinical trials is warranted .
- [VIRTUAL] SAFETY, TOLERABILITY AND PHARMACOKINETICS OF KL060332, A CLASS I HBV CAPSID ASSEMBLY MODULATOR, IN HEALTHY PARTICIPANTS () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1076;
Further investigation of the strategy to combine HBV siRNA with ASO and STOPS compounds in human clinical trials is warranted . KL060332 displayed a favorable safety, tolerability and PK profile suitable for further clinical development .
- ALG-000184 / Aligos Therap
[VIRTUAL] SAFETY, PHARMACOKINETICS (PK), AND ANTIVIRAL ACTIVITY OF THE CAPSID ASSEMBLY MODULATOR (CAM) ALG-000184 IN SUBJECTS WITH CHRONIC HEPATITIS B (CHB) () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1075;
In CNT/TN CHB subjects, 100 mg of ALG-000184 given for 28 days was well tolerated, exhibited predictable PK properties, and resulted in HBV DNA and RNA levels <LLOQ for most subjects. Additional doses are being evaluated in ongoing cohorts .
- [VIRTUAL] ALG-005398 IS A POTENT NON-HAP CLASS I HBV CAPSID ASSEMBLY MODULATOR THAT STRONGLY REDUCES HBsAg LEVELS IN VIVO () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1050;
ALG-005398 is the first non-HAP Class I CAM reported to date and showed excellent in vitro and in vivo antiviral activity, including a pronounced HBsAg reduction in vivo . The minimal ALT elevation and paced antiviral kinetics make this an attractive chemotype for further development .
- | Journal: Recombinant Turnip Yellow Mosaic Virus Coat Protein as a Potential Nanocarrier. (Pubmed Central) - Oct 20, 2021
The C-terminal tail which is exposed on the surface can be exploited as a useful site to display multiple copies of functional ligands. The ability of the chimeric VLPs to self-assemble after undergo chemical denaturation indicates its potential role to serve as a nanocarrier for use in targeted drug delivery.
- | Journal: Atomic Structure of the Trichomonas vaginalis Double-Stranded RNA Virus 2. (Pubmed Central) - Oct 13, 2021
Our results reveal the intersubunit interactions driving CSP association for capsid assembly and the properties that govern organization and maintenance of the viral genome. Structural comparison between TVV2 capsids and those of distantly related dsRNA viruses indicates conserved strategies of nascent RNA release and a putative viral guanylyltransferase domain implicated in the cytoplasmic maintenance of viral messenger and genomic RNA.
- | BI2536 / Boehringer Ingelheim
Journal: Antiviral activity of PLK1-targeting siRNA delivered by lipid nanoparticles in HBV-infected hepatocytes. (Pubmed Central) - Oct 8, 2021
Structural comparison between TVV2 capsids and those of distantly related dsRNA viruses indicates conserved strategies of nascent RNA release and a putative viral guanylyltransferase domain implicated in the cytoplasmic maintenance of viral messenger and genomic RNA. This study emphasizes that a specific PLK1 inhibition could help achieving an improved HBsAg loss in CHB patients, likely in combination with other HBsAg-targeting strategies.
- || GST-HG141 / Fujian Cosunter
Clinical, P1 data, PK/PD data, Journal: Safety, tolerability, and pharmacokinetics of the novel hepatitis B virus capsid assembly modulator GST-HG141 in healthy Chinese subjects: a first-in-human single- and multiple-dose escalation trial. (Pubmed Central) - Sep 24, 2021
P1
GST-HG141 was tolerated in healthy Chinese subjects. The safety and PK profiles of GST-HG141 support the further evaluation of its efficacy in individuals with CHB.
- | Journal: Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays. (Pubmed Central) - Sep 23, 2021
In bimolecular fluorescence complementation (BiFC) assay, compound II-2-9 inhibited the HBV by disrupting the HBV capsid interactions. In summary, this study provides a highly efficient way to discover novel CAMs, and 2-aryl-4-quinolyl amide derivatives could serve as the starting point for development of novel anti-HBV drugs.
- | Journal: RNA Binding Properties of the Ty1 LTR-Retrotransposon Gag Protein. (Pubmed Central) - Sep 17, 2021
We also uncover a relationship between Ty1 RNA structure and Gag binding involving the pseudoknot present on Ty1 gRNA. In all likelihood, the differences in Gag binding affinity detected in vitro only partially explain selective Ty1 RNA packaging into VLPs in vivo.
- | Journal: Bombyx mori nucleopolyhedrovirus Bm46 is essential for efficient production of infectious BV and nucleocapsid morphogenesis. (Pubmed Central) - Sep 10, 2021
qRT-PCR and Western blot analysis showed that the expression of VP39 was affected by Bm46 disruption. Taken together, our findings clearly pointed out that Bm46 played an important role in BV production and the proper formation of nucleocapsid morphogenesis.
- | Journal: Curvature of the Retroviral Capsid Assembly Is Modulated by a Molecular Switch. (Pubmed Central) - Sep 9, 2021
These residues undergo large torsion angle changes, resulting in a 34° rotation of the C-terminal domain relative to its N-terminal domain around the flexible interdomain linker, without substantial changes of either the conformation of individual domains or the assembly contact interfaces. This knowledge provides new insights to help decipher the mechanism of the retroviral capsid assembly.
- | Journal: Characterization of Viral Genome Encapsidated in Adeno-associated Recombinant Vectors Produced in Yeast Saccharomyces cerevisiae. (Pubmed Central) - Sep 4, 2021
However, the majority of encapsidated DNA consists of fragmented regions of the transgene cassette, with ITRs being the most represented sequences. Altogether, these data indicate that, in yeast, encapsidation occurs with low efficiency and that rAAVs resemble pseudo-vectors that are present in clinical-grade rAAV preparations.
- | Journal: Identification of a new class of HBV capsid assembly modulator. (Pubmed Central) - Sep 3, 2021
The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.
- | RG7907 / Roche
Journal: What drives the dynamics of HBV RNA during treatment? (Pubmed Central) - Sep 2, 2021
This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly and profoundly reduce HBV RNA...We compare the predictions with those obtained in patients treated with the nucleotide analog tenofovir...The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral suppressed patients where HBV DNA is no longer detectable.
- | Journal: HBV Core Protein Is in Flux between Cytoplasmic, Nuclear, and Nucleolar Compartments. (Pubmed Central) - Aug 28, 2021
Localization is primarily a function of time, core protein concentration, and assembly. This has important implications for our understanding of the mechanisms of antivirals that target HBV capsid assembly.
- || JNJ-56136379 / J&J
Clinical, Journal, Monotherapy: Virology analysis of chronic hepatitis B infected patients treated for 28 days with JNJ-56136379 monotherapy. (Pubmed Central) - Aug 27, 2021
P1
In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ-6379 in-vitro activity were rare, with no consistent impact on virological response during a 4 week phase 1b study. Emergence of resistance to longer treatments of JNJ-6379 will be evaluated in phase 2 studies.
- | Journal: Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches. (Pubmed Central) - Aug 18, 2021
In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.
- | Journal: All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery. (Pubmed Central) - Aug 15, 2021
A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.