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- | Journal: A Unique Role of the Human Cytomegalovirus Small Capsid Protein in Capsid Assembly. (Pubmed Central) - Oct 29, 2022
In summary, our data contribute to the understanding of how SCP plays an essential part in the HCMV infection cycle. Moreover, disrupting the SCP-MCP interface may provide a starting point for the development of novel antiviral drugs.
- || Review, Journal: Nuclear entry and egress of parvoviruses. (Pubmed Central) - Oct 26, 2022
An alternative pathway for nuclear export has been described using active transport through the NPC mediated by the chromosome region maintenance 1 protein, CRM1, which is enhanced by phosphorylation of the N-terminal domain of VP2. However, other alternative but not yet uncharacterized nuclear export pathways cannot be excluded.
- | Journal: Marine viral particles reveal an expansive repertoire of phage-parasitizing mobile elements. (Pubmed Central) - Oct 25, 2022
In total, the data suggest that marine phage satellites have potential to significantly impact the ecology and evolution of bacteria and their viruses throughout the oceans. We predict that any habitat that harbors bacteriophage will also harbor similar phage satellites, making them a ubiquitous feature of most microbiomes on Earth.
- NOVEL ULTRA-POTENT CAPSID ASSEMBLY MODULATORS PREVENT ABNORMAL ACCUMULATION OF EMPTY CAPSIDS AND ASSOCIATED T-CELL MEDIATED LIVER INJURY IN A MOUSE MODEL OF HEPATITIS B VIRUS INFECTION () - Oct 23, 2022 - Abstract #AASLD2022AASLD_722;
This suggests that CAMs fostering an EC-accumulating phenotype may generate targets of inadequate immunopathology. Conversely, the lack of cytoplasmic EC accumulation that typifies the in vivo behavior of ATI-1428 or ATI-1645 should not interfere with productive T cell–mediated viral clearance.
- RG7907 / Roche, ALG-005398 / Aligos Therap
NON-HAP CLASS I CAPSID ASSEMBLY MODULATORS HAVE DISTINCT PROFILES AND A DIFFERENTIATED MECHANISM OF ACTION () - Oct 23, 2022 - Abstract #AASLD2022AASLD_704;
Their underlying mechanisms of action governing in vivo HBsAg reduction are also clearly differentiated. Since optimized non-HAP CAM1s have suitable ADME / tox profiles, they represent an attractive class of molecules for further development as a part of potential functional cure regimens for CHB, offering a potential advantage over HAPs.
- NOVEL FURANOCOUMARINS TARGET CCCDNA TO INHIBIT HBV DNA REPLICATION AND VIRAL GENE EXPRESSION () - Oct 23, 2022 - Abstract #AASLD2022AASLD_699;
Furanocoumarins FC-20 and FC-31 are effective in suppressing HBV replication and viral gene expression. These compounds should be further evaluated for their therapeutic potential.
- RG7907 / Roche
HAP CLASS I CAPSID ASSEMBLY MODULATORS CLEAR HEPATITIS B VIRUS-INFECTED HEPATOCYTES THROUGH CORE-DEPENDENT HEPATOCYTE DEATH AND SUBSEQUENT PROLIFERATION () - Oct 23, 2022 - Abstract #AASLD2022AASLD_698;
Compensatory hepatocyte proliferation leads to an additional loss of AAV-HBV episomes. The combination of both mechanisms, possibly complemented by an immune response, results in a sustained loss of HBV-positive cells.
- Lynparza (olaparib) / Merck (MSD), AstraZeneca
OLAPARIB ENHANCES THE ANTI-VIRAL EFFECT OF CRISPR/Cas9 THERAPY TARGETING HBV GENOME VIA NHEJ-MEDIATED DNA REPAIR MACHINERY () - Oct 23, 2022 - Abstract #AASLD2022AASLD_662;
Four days after HBV infection, Cas9 expression was induced by doxycycline (DOX) administration...Treatment of entecavir, interferon α, Bay41-4109 (Capsid Assembly Modulator) did not alter the efficacy of CRISPR/Cas9 treatment in HepG2-hNTCP-iCas9 cells... Inhibition of NHEJ-mediated DNA repair machinery with olaparib enhances the efficacy of CRISPR/Cas9 treatment targeting HBV genome.
- ABI-4334 / Assembly Biosci
ABI-4334, A NOVEL HEPATITIS B VIRUS CORE INHIBITOR, ACCELERATES CAPSID ASSEMBLY AND INHIBITS CCCDNA FORMATION VIA MULTIPLE PATHWAYS () - Oct 23, 2022 - Abstract #AASLD2022AASLD_615;
During early stages of HBV infection, 4334 prematurely disrupts both RC-DNA and DL-DNA containing capsids. A Phase 1a first-in-human study with 4334 is planned for 2H-2022.
- | JNJ-3989 / J&J
Clinical Trial,Phase II, Journal: Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB. (Pubmed Central) - Oct 20, 2022
P1/2
A Phase 1a first-in-human study with 4334 is planned for 2H-2022. JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose.
- | Journal: Antiviral activities of Polygonum Perfoliatum L. extract and related phenolic acid constituents against hepatitis B virus. (Pubmed Central) - Oct 18, 2022
Further study showed that the phenolic acids constituents, protocatechuic acid and gallic acid, but not ethyl caffeate, which are reported enriched in the water extract fraction, showed strong anti-HBV activities in inhibiting viral core DNA synthesis, CCC DNA formation and HBeAg production. These results suggested that the Polygonum perfoliatum L. total extract and the related phenolic acids like protocatechuic acid and gallic acid could inhibit HBV replication and also indicated the potential utility of Polygonum perfoliatum L. and related constituents as sources of novel antivirals against HBV.
- | Journal: Filovirus helical nucleocapsid structures. (Pubmed Central) - Oct 16, 2022
Mini-abstract Filovirus nucleocapsid is responsible for viral genome transcription and replication. Here, we summarize the helical nucleocapsid structure of Ebola and Marburg viruses, focusing on the nucleoprotein-RNA helix of the nucleocapsid core structure, which has been recently determined by cryo-electron microscopy.
- Irsp53 facilitates Arc capsid assembly and release during long-term potentiation (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_6773;
Using imaging of live neurons, we find that Arc and IRSp53 colocalize and traffic anterograde from soma to dendrites, sometimes followed by loss of signal that may be release events. These results help elucidate the molecular mechanisms that facilitate Arc capsid assembly and release, identifying a potentially new secretory pathway in neurons.
- | Journal: Multiscale Modeling of Hepatitis B Virus Capsid Assembly and Its Dimorphism. (Pubmed Central) - Oct 4, 2022
By constructing Markov state models and employing transition path theory, we identify pathways leading to T = 3, T = 4, and other experimentally observed capsid morphologies. The analysis shows that capsid polymorphism is promoted by the low HBV capsid bending modulus, where the key factors controlling polymorphism are the conformational energy landscape and protein-protein binding affinities.
- | Journal: The Contribution of Kaposi's Sarcoma-Associated Herpesvirus ORF7 and Its Zinc-Finger Motif to Viral Genome Cleavage and Capsid Formation. (Pubmed Central) - Oct 1, 2022
To our knowledge, this is the first report showing ORF7-KO-induced soccer ball-like capsids production and ORF7 function in the KSHV capsid assembly process. Our findings provide insights into the role of ORF7 in KSHV capsid formation.
- | Preclinical, Journal: Importance of RNA length for in vitro encapsidation by the nucleoprotein of human Respiratory Syncytial Virus. (Pubmed Central) - Sep 30, 2022
Finally, we showed that RNA encapsidation is crucial for the in vitro reconstitution of pseudo-viral factories. Together, our findings provide insight into RSV viral genome encapsidation specificity.
- | Journal: Reovirus uses temporospatial compartmentalization to orchestrate core versus outercapsid assembly. (Pubmed Central) - Sep 30, 2022
Moreover, late during infection, +RNA pools largely contributed to the production of de-novo viral proteins and fully-assembled infectious viruses. Altogether the results suggest an advanced model of reovirus replication with spatiotemporal segregation of core amplification, OC complexes and fully assembled virions.
- | Hepcludex (bulevirtide) / Gilead
Journal: Cautious optimism in anticipation of hepatitis B curative therapies. (Pubmed Central) - Sep 29, 2022
The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen. Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection, which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.
- | Journal: Tuning the Dynamics of Viral Factories-Inspired Compartments Formed by Peptide-RNA Liquid-Liquid Phase Separation. (Pubmed Central) - Sep 23, 2022
Moreover, by taking this approach to the next step, we developed liquid compartments with light-induced tunable dynamics. Our results demonstrate that the material properties of liquid droplets can be temporally regulated by increasing peptide polarity and charge, and that these changes can be further utilized for controlled partitioning and release of payloads from the compartments.
- | Journal: Characterization of a Primordial Major Capsid-Scaffolding Protein Complex in Icosahedral Virus Shell Assembly. (Pubmed Central) - Sep 21, 2022
A model is described wherein dynamic interactions between MCP proteins play an essential role in high fidelity viral shell assembly. Scaffold-chaperoned MCP polymerization is a strongly conserved process in all the large dsDNA viruses and our results provide insight into this primordial complex in solution and have broad biological significance in our understanding of virus assembly mechanisms.
- | Journal: Role of VP30 Phosphorylation in Ebola Virus Nucleocapsid Assembly and Transport. (Pubmed Central) - Sep 20, 2022
Our work determines the localization of VP30 at the surface of ruffled nucleocapsids, which differs from the localization of polymerase in EBOV-infected cells. This study sheds light on the novel role of VP30 phosphorylation in nucleocapsid assembly, which is an important prerequisite for virion formation.
- | Journal: Design, synthesis and biological evaluation of novel dihydrobenzodioxine derivatives as HBV capsid protein inhibitors. (Pubmed Central) - Sep 14, 2022
Compound 5a (EC = 0.50 ± 0.07 μM, CC = 48.16 ± 9.15 μM) showed better anti-HBV DNA replication activity than the lead compound BA-38017, and showed good inhibitory effect on the assembly of HBV capsid protein compared with the clinical drug NVR 3-778. In addition, preliminary structure-activity relationship (SAR) and molecular docking studies were conducted to explore potential interactions and binding modes between compounds and target proteins, which may help researchers to find more effective anti-HBV drugs.
- | bersacapavir (JNJ-56136379) / J&J
Journal: Drug-Drug Interactions With the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379 (Bersacapavir). (Pubmed Central) - Sep 7, 2022
P1
Overall, these results demonstrated that a strong CYP3A inhibitor (itraconazole) modestly increased JNJ-56136379 exposure. Furthermore, JNJ-56136379 was a weak inducer of CYP3A (midazolam) and increased ethinyl estradiol exposure; coadministration of high-dose estrogen-based contraceptives and JNJ-56136379 is not recommended.
- | Journal: Structures of L-BC virus and its open particle provide insight into Totivirus capsid assembly. (Pubmed Central) - Aug 24, 2022
The existence of the open particles together with domain swapping within a decamer provides evidence that Totiviridae capsids assemble from the decamers of capsid proteins. Furthermore, the open particles may be assembly intermediates that are prepared for the incorporation of the virus (+) strand RNA.
- | Journal: Discovery and Antiviral Profile of New Sulfamoylbenzamide Derivatives as HBV Capsid Assembly Modulators. (Pubmed Central) - Aug 24, 2022
When studied in a transgenic mouse model of hepatic HBV replication, it was considerably more potent than NVR 3-778, the first sulfamoylbenzamide (SBA) CAM that entered clinical trials for CHB, at reducing viral replication in a dose-dependent fashion. We present herein the discovery process, the SAR analysis and the pre-clinical profile of this novel SBA CAM.
- | trifluoperazine / Generic mfg.
Journal: Discovery of novel druggable pockets on polyomavirus VP1 through crystallographic fragment-based screening to develop capsid assembly inhibitors. (Pubmed Central) - Aug 22, 2022
For each pocket, we derive pharmacophore features which enable the design of small molecules preventing the interaction between VP1 pentamers and therefore inhibiting capsid assembly. Our data lay a foundation towards a rational development of first-in-class drugs targeting polyomavirus capsid.
- || Zokinvy (lonafarnib) / Eiger
Review, Journal: Future anti-HDV treatment strategies, including those aimed at HBV functional cure. (Pubmed Central) - Aug 11, 2022
Drugs only active against HDV, such as lonafarnib, have shown efficacy in combination with nucleoside analogues and peginterferon, but do not lead to HBsAg loss...Immunomodulators on their own seldom achieve functional cure, hence these agents in combination to assess the optimal combination are being investigated. Consequently, agents leading to functional cure of HBV are ideal for both HBV and HDV.
- | Journal: Conformational ensemble of the full-length SARS-CoV-2 nucleocapsid (N) protein based on molecular simulations and SAXS data. (Pubmed Central) - Aug 10, 2022
Each of the intrinsically disordered regions adopts conformations that are locally compact, yet on average, much more extended than Gaussian chains of equivalent lengths. We offer a detailed picture of the conformational ensemble of the nucleocapsid protein dimer under near-physiological conditions, which will be important for understanding the nucleocapsid assembly process.
- AB-836 / Arbutus
Rational design of a novel series of HBV capsid inhibitors leading to the identification of clinical candidate AB-836 (W183a (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_11435;
Initial data from a phase 1b proof of concept study in chronic hepatitis B patients receiving a once daily 100 mg dose of AB-836 for 28 days (N=4) showed robust antiviral activity with a mean reduction of 3.1 log10 in HBV DNA from baseline. The excellent preclinical profile and emerging clinical data support further development of AB-836.
- morphothiadine mesilate (GLS4) / HEC Pharm
Computational prediction of susceptibility and resistance for HBV capsid assembly effectors (Hall F2 (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_9079;
The results also suggest that GLP-26 will possess broad anti-HBV activity, more so than GLS4. This study demonstrates the utility of computational resistance prediction in the context of drug discovery, which can be applied to many viral protiens.
- Predicting the mechanism of action of HBV capsid assembly modulators from a combination of molecular dynamics and machine learning (S401a (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_4416;
Novel insights into the structural differences between apo and CAM-bound intermediates are obtained. These models can be used to better understand structural transitions that govern nucleocapsid assembly as well as for selection of structures from molecular dynamics simulations for subsequent docking.
- | Journal: Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model. (Pubmed Central) - Jul 29, 2022
Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment.
- | Journal: Diazepinone HBV Capsid Assembly Modulators. (Pubmed Central) - Jul 28, 2022
Interfering with capsid assembly has shown efficacy in clinical trials with small molecule capsid assembly modulators (CAMs). Herein is described the further optimization of a progressive series of diazepinone HBV CAMs.
- || ALG-000184 / Aligos Therap
$ALGS Aligos Therapeutics Initiates 12-Week Dosing Cohort in Phase 1b Study Evaluating Its Class II Capsid Assembly Modulator, ALG-000184 https://t.co/F2d9N6kkgN (Twitter) - Jul 25, 2022
- | Journal: Autophagic membranes participate in hepatitis B virus nucleocapsid assembly, precore and core protein trafficking, and viral release. (Pubmed Central) - Jul 23, 2022
HBV induces the fusion of autophagosomes and multivesicular bodies and the silencing of Rab11, a regulator of this fusion, is associated with the reduction of release of mature HBV particles. Our studies thus indicate that autophagic membranes participate in the assembly of HBV nucleocapsids, the trafficking of HBV precore and core proteins, and likely also the egress of HBV particles.
- | Journal: The Dynamics of Viruslike Capsid Assembly and Disassembly. (Pubmed Central) - Jul 23, 2022
We explain our experimental findings using a simple model based on classical nucleation theory applied to virus capsids, in which we account for the change in the free protein concentration, as the different types of shells assemble and disassemble by shedding or absorbing single protein subunits. As far as we are aware, this is the first study confirming that both the assembly and disassembly of viruslike shells can be explained through classical nucleation theory, reproducing quantitatively results from time-resolved experiments.
- | Cavatak (CVA21) / Merck (MSD)
Preclinical, Journal: Binding of Coxsackievirus A21 procapsids to immobilized glutathione depends on cell culture conditions during infection. (Pubmed Central) - Jul 23, 2022
However, at sub-physiological temperature or after removal of serum at infection, both procapsids and mature virions bound and co-eluted from the immobilized glutathione ligand. This work may improve the understanding of CVA21 capsid assembly and presents an efficient purification method that may be applied to picornaviruses that interact with intracellular GSH.
- | Journal: Delineation of an epitope recognized by a chikungunya virus anti-capsid monoclonal antibody on the protease domain using an immuno-informatics approach. (Pubmed Central) - Jul 15, 2022
The binding specificity of the mAb highlights the possibility of using this anti-CP antibody for therapeutic or prophylactic treatment against CHIKV. Communicated by Ramaswamy H. Sarma.
- | Journal: Development and Characterization of an Inducible Assay System to Measure Zika Virus Capsid Interaction. (Pubmed Central) - Jul 14, 2022
By using of this system, peptides (Pep.15-24 in the N-terminal region of ZIKV capsid protein and Pep.44-58 in the ?2 helix of ZIKV capsid protein) were identified to inhibit ZIKV capsid-capsid interaction. Overall, this study developed a novel inducible assay system to measure ZIKV capsid interaction and identify ZIKV capsid multimerization inhibitors, which will be applied for future discovery of ZIKV assembly inhibitors.
- || Review, Journal, IO biomarker: Getting to HBV cure: the promising paths forward. (Pubmed Central) - Jun 22, 2022
Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs, and discusses the limitations and unanswered questions on the journey to HBV cure.
- | Journal: Insights into the capsid structure of banana bunchy top virus. (Pubmed Central) - Jun 14, 2022
Comparison with the CP and capsid structure of geminiviruses provided useful insights into the mode of nucleic acid binding and the role of genome during capsid assembly. The online version contains supplementary material available at 10.1007/s13205-022-03204-4.
- || JNJ-73763989 / J&J, bersacapavir (JNJ-56136379) / J&J
PK/PD data, Journal: JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B. (Pubmed Central) - Jun 14, 2022
P1, P1/2
JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
- JNJ-73763989 / J&J, bersacapavir (JNJ-56136379) / J&J
Efficacy and safety of finite 48-week treatment with the siRNA JNJ-3989 and the capsid assembly modulator (CAM-N) JNJ-6379 in HBeAg negative virologically suppressed (VS) chronic hepatitis B (CHB) patients: results from REEF-2 study (Auditorium) - Jun 11, 2022 - Abstract #EASLILC2022EASL_ILC_2526;
All treatment including NA was discontinued after 48 weeks. The primary endpoint was the proportion of patients achieving HBsAg
- | Journal: Identification of acridinedione scaffolds as potential inhibitor of DENV-2 C protein: An in silico strategy to combat dengue. (Pubmed Central) - May 29, 2022
Therefore, we intend to suggest that the DSPD3 molecule could be used as a potential therapeutic molecule against dengue complications as compared to the cocrystallized inhibitor ST-148. However, further studies are required to demonstrate the ability of DSPD3 to induce DENV-2 C tetramer formation.
- || entecavir / Generic mfg.
Review, Journal: How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development? (Pubmed Central) - May 27, 2022
The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.
- | Journal: Transient RNA Interactions Leave a Covalent Imprint on a Viral Capsid Protein. (Pubmed Central) - May 20, 2022
In particular, it enables the redox-dependent regulation of the exposure of the C-terminal extension on the capsid surface, which is required for nuclear uptake of the capsid. Phylogenetic analysis of capsid proteins from hepadnaviruses points toward a function of this switch in the persistence of HBV infections.
- | Journal: Developing all-in-one virus-like particles for Cas9 mRNA/single guide RNA co-delivery and aptamer-containing lentiviral vectors for improved gene expression. (Pubmed Central) - May 18, 2022
We further improved LVs for integrated gene expression by including an aptamer sequence in lentiviral genomic RNA, which improved lentiviral particle production and enhanced LV genomic RNA packaging. In summary, here we describe the development of new all-in-one VLPs for co-delivery of Cas9 mRNA and sgRNA, and new LVs for enhanced vector production and gene expression.
- | Preclinical, Journal: Dysregulation of Hepatitis B Virus Nucleocapsid Assembly in vitro by RNA-binding Small Ligands. (Pubmed Central) - May 12, 2022
This also allows for computational exploration of potential synergic effects between anti-viral ligands directed at distinct molecular targets in vivo. HBV PS-regulated assembly can be dysregulated by novel small molecule RNA-binding ligands opening a novel target for developing directly-acting anti-virals against this major pathogen.
- RG7907 / Roche
Viral nucleic acids suppression activity of RO7049389 plus NUC with/without Peg-IFN in virologically-suppressed and naive chronic hepatitis B patients: 48-week treatment and post-treatment follow up (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_2364;
P1
RO7049389+NUC ± Peg-IFN demonstrated potent effect on viral nucleic acids suppression even in treatment naïve patients. HBV DNA was suppressed and maintained 2 log10- copies/ml below baseline after the cessation of RO7049389, which may suggest a certain level of suppression in cccDNA level/ transcriptional activity in treatment naïve patients.
- The discovery of AMS-I-1274, a high potent and orally active capsid-assembly modulator against hepatitis B virus (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_2303;
HBV DNA was suppressed and maintained 2 log10- copies/ml below baseline after the cessation of RO7049389, which may suggest a certain level of suppression in cccDNA level/ transcriptional activity in treatment naïve patients. Taken together, these data support that AMS-I-1274 is a novel class II capsid inhibitor with high anti-HBV potency and a favorable preclinical profile for clinical advancement.