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- | 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.
- GST-HG141 / Fujian Cosunter
Safety, pharmacokinetics and antiviral activity of GST-HG141, a hepatitis B virus capsid assembly modulator, in subjects with chronic hepatitis B (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_2245;
P1
It resulted in rapid, robust and dose-dependent decline in serum HBV DNA. Serum HBV pgRNA levels also decreased significantly.
- JNJ-73763989 / J&J, bersacapavir (JNJ-56136379) / J&J
Effects of the siRNA JNJ-3989 and/or the capsid assembly modulator (CAM-N) JNJ-6379 on viral markers of chronic hepatitis B (CHB): results from the REEF-1 study (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_1932;
P2b
Treatment with JNJ-3989 reduced levels of HBV markers in a dose dependent manner. Reductions in viral markers were most pronounced in NCT HBeAg+ patients.
- | Journal: Dataset of high-throughput ligand screening against the RNA Packaging Signals regulating Hepatitis B Virus nucleocapsid formation. (Pubmed Central) - May 7, 2022
The results imply that ∼50% of the compounds prevent complete NCP formation, highlighting both PS-meditated assembly and the PS-binding compounds as potential directly-acting anti-virals with a novel molecular target. Importantly, this method allows high-throughput in vitro screening for assembly inhibitors in this major human pathogen.
- || JNJ-64530440 / J&J
Clinical, PK/PD data, Clinical Trial,Phase I, Journal: Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers. (Pubmed Central) - May 6, 2022
P1
Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.
- Strength of Subunit Association Dictates AAP Requirement for AAV Capsid Assembly (Poster Board Number: Tu-8; Hall D) - May 6, 2022 - Abstract #ASGCT2022ASGCT_1750;
Conversely, VP proteins with relatively lower propensity to associate at the 2-fold and 5-fold axis would need non-VP factors for stabilization and therefore depend on AAP for capsid assembly. Together, our findings indicate a model where AAP aids inter-subunit associations; whereas AAP-independent AAV variants have enhanced VP subunit associations at the VP-VP interface, thereby capable of assembling capsid in the absence of AAP.
- Engineering AAV Capsids with CNS-Targeted Biodistribution from Massively Diverse Libraries Using Machine Learning (Poster Board Number: M-11; Hall D) - May 6, 2022 - Abstract #ASGCT2022ASGCT_1596;
In total, we advanced 5000 capsid variants and controls into an NHP secondary screen that profiles both DNA and RNA to measure functional, cell-type-specific transduction within the target tissue. The AAVidTM platform significantly advances the magnitude of novel capsid screening power and computational analysis to identify next-generation AAV capsids with tissue- and cell type-specific biodistribution.
- Identification of an N-Terminal Degron and its Leucine Residue in the AAV AAP Protein Critical for its Promoted Degradation (Poster Board Number: W-30; Hall D) - May 6, 2022 - Abstract #ASGCT2022ASGCT_1432;
In summary, our observations strongly support a model that the AAP HR is an N-terminal degron whose positioning and its leucine residue at position 25 drive its degron function. Further studies are warranted to understand the functional significance of the AAP's degron activity in AAV capsid assembly and what types of post-translational modifications and pathways mediate AAP degradation.
- | lenacapavir (GS CA2) / Gilead
Journal: HIV Capsid Protein Genetic Diversity Across HIV-1 Variants and Impact on New Capsid-Inhibitor Lenacapavir. (Pubmed Central) - May 3, 2022
We present a thorough analysis of p24 variability among all HIV-1 variants circulating to date. Since p24 genetic variability can impact the viral replication cycle and the efficacy of new p24-based diagnostic, therapeutic, and vaccine strategies, conservation studies must consider all HIV-1 variants circulating worldwide.
- | Journal: The N-terminal region (VP4) of the foot-and-mouth disease capsid precursor (P1-2A) is not required during its synthesis to allow subsequent processing by the 3C protease. (Pubmed Central) - Apr 29, 2022
Cleavage of this truncated precursor by 3C at the VP3/VP1 and VP2/VP3 junctions occurred efficiently. Thus, in contrast to the presence of the YCPRP motif in VP1, there are no critical motifs near the N-terminus of the precursor, within VP4, required for correct cleavage by 3C.
- | Journal: Inhibitory Activities of Ranunculus japonicus Thunb. Ethanol Extract against Hepatitis B Virus. (Pubmed Central) - Apr 20, 2022
Together, this study found that Ranunculus japonicus Thunb. extract could inhibit HBV replication at multiple steps, especially showed significant inhibitory effects on capsid assembly and CCC DNA formation.
- | Preclinical, Journal: In vitro selection of high affinity DNA and RNA aptamers that detect hepatitis C virus core protein of genotypes 1 to 4 and inhibit virus production in cell culture. (Pubmed Central) - Apr 19, 2022
Additionally, the two most prevalent and high affinity aptamers were assayed in Huh-7.5 reporter cell lines infected with HCV, where they decreased both the viral progeny titer and the extracellular viral RNA level, while increasing the amount of intracellular viral RNA. Our results suggest that these aptamers inhibit HCV capsid assembly and virion formation, thus making them good candidate molecules for the design of novel therapeutic approaches for hepatitis C.
- | AB-506 / Arbutus
Journal: The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly. (Pubmed Central) - Apr 19, 2022
Herein we report the further optimisation of clinical candidate AB-506 through core modification with a focus on increasing oral exposure and oral half-life. Maintenance of high levels of anti-HBV cellular potency in conjunction with improvements in pharmacokinetic properties led to multi-log reductions in serum HBV DNA following low, once-daily oral dosing for key analogues in a preclinical animal model of HBV replication.
- | Journal: Acetophenone 4-nitrophenylhydrazone inhibits Hepatitis B virus replication by modulating capsid assembly. (Pubmed Central) - Apr 15, 2022
Biochemical assays using a truncated core protein consisting of the assembly domain showed that ANPH accelerates the formation of morphologically intact capsids. Taken together, we propose that ANPH might provide a new structural scaffold to design a new anti-HBV drug in medicinal chemistry as well as chemical probes for HBV core protein functions in the future.
- | Journal: Oligomers of hepatitis A virus (HAV) capsid protein VP1 generated in a heterologous expression system. (Pubmed Central) - Apr 15, 2022
Taken together, we propose that ANPH might provide a new structural scaffold to design a new anti-HBV drug in medicinal chemistry as well as chemical probes for HBV core protein functions in the future. VP1 oligomers generated in the bacterial expression system can be utilized for understanding the molecular pathway of HAV capsid assembly and may also have potential biomedical usages in prevention and diagnostics of HAV infections.
- | Journal: Structural basis of bacteriophage lambda capsid maturation. (Pubmed Central) - Apr 13, 2022
Upon conformational expansion of the capsid shell, the missing top layer is fulfilled by cementing the gpD protein against the internal pressure of DNA packaging. Our structures illuminate the assembly mechanisms of dsDNA viruses.
- | Journal: The Mechanism of Action of Hepatitis B Virus Capsid Assembly Modulators Can Be Predicted from Binding to Early Assembly Intermediates. (Pubmed Central) - Apr 12, 2022
Finally, the potency of CAMs within the same class was studied. We find that an increased number of contacts with the capsid protein and favorable binding energies inferred from free energy perturbation calculations are indicative of increased potency.
- | Journal: Hysteresis in Hepatitis B Virus (HBV) Requires Assembly of Near-Perfect Capsids. (Pubmed Central) - Apr 7, 2022
These results suggest that hysteresis arises from an ideal capsid lattice, even when some of the substituents in that lattice have defects. Consistent with structural studies that show a subtle difference between Cp dimers and Cp in capsid, we propose that hysteresis arises when HBV capsids undergo a lattice-dependent structural transition.
- | Journal: Lentiviral Capsid-Mediated Streptococcus pyogenes Cas9 Ribonucleoprotein Delivery for Efficient and Safe Multiplex Genome Editing. (Pubmed Central) - Apr 5, 2022
Thus, in addition to better safety features, the Cas9 VLPs are especially suited for multiplex genome editing. In summary, our VLPs offer safe, efficient, and flexible multiplex genome editing.
- | Journal: Cryo-EM structure of the cetacean morbillivirus nucleoprotein-RNA complex. (Pubmed Central) - Apr 5, 2022
The CeMV structure reveals exclusive interactions leading to more extensive protomer-RNA and protomer-protomer interfaces. We identified twelve residues, among those varying between CeMV strains, as putatively important for the stabilization of the RNP complex, which highlights the need to study the potential of CeMV N mutations that modulate nucleocapsid assembly to also affect viral phenotype and host adaptation.
- || JNJ-64530440 / J&J
Clinical, PK/PD data, Journal, Monotherapy: Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection. (Pubmed Central) - Apr 2, 2022
P1
We identified twelve residues, among those varying between CeMV strains, as putatively important for the stabilization of the RNP complex, which highlights the need to study the potential of CeMV N mutations that modulate nucleocapsid assembly to also affect viral phenotype and host adaptation. JNJ-64530440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved potent antiviral activity in CHB patients.
- | Journal: An in silico study to unveil potential drugs and vaccine chimera for HBV capsid assembly protein: combined molecular docking and dynamics simulation approach. (Pubmed Central) - Mar 31, 2022
It was revealed that the vaccine is showing a very good affinity of binding for the TLR3 and forming a network of hydrophobic and hydrophilic interactions. Overall, the findings of this study are promising and might be useful for further experimental validations.
- | Journal: UL25 capsid binding facilitates mechanical maturation of the Herpesvirus capsid and allows retention of pressurized DNA. (Pubmed Central) - Mar 29, 2022
We show that UL25 binding provides the critical capsid reinforcement required for stable DNA encapsidation. Our data also suggests that gradual capsid reinforcement by progressive UL25 binding is a feasible capsid maturation mechanism, correlated with DNA packaging progression.
- | Journal: CryoEM structure of the Nipah virus nucleocapsid assembly. (Pubmed Central) - Mar 25, 2022
The structure reveals commonalities in RNA binding pockets and in the conformation of bound RNA, not only with members of the Paramyxoviridae family, but also with the evolutionarily distant Filoviridae Ebola virus. Significant structural differences with other Paramyxoviridae members are also observed, particularly in the position and length of the exposed α-helix, residues 123-139, which may serve as a valuable epitope for surveillance and diagnostics.
- | Journal: Insights into the specificity for the interaction of the promiscuous SARS-CoV-2 nucleocapsid protein N-terminal domain with deoxyribonucleic acids. (Pubmed Central) - Mar 23, 2022
We showed a preference for TRS in the formation of liquid condensates when compared to NS. Moreover, our results on DNA binding may serve as a starting point for the design of inhibitors, including aptamers, against N, a possible therapeutic target essential for the virus infectivity.
- || Review, Journal: Targeting the Virus Capsid as a Tool to Fight RNA Viruses. (Pubmed Central) - Mar 23, 2022
Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.
- | Journal: Discovery of SHR5133, a Highly Potent and Novel HBV Capsid Assembly Modulator. (Pubmed Central) - Mar 19, 2022
Lead optimization resulted in compound 8 with an EC value of 511 nM, and then methyl substitution on the piperazine was found to improve the in vitro potency remarkably. Further SAR studies established the key compound SHR5133, which showed high in vitro antiviral potency, favorable pharmacokinetic profiles across species, and robust in vivo efficacy.
- HEC121120 / HEC Pharm
HEC121120, a novel allosteric modulator of HBV core protein demonstrates potent antiviral activities in vitro and in vivo (Poster Area) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1763;
In PHH isolated from chronically infected humanized liver mouse, 14 days of GLS4 (5 μM) and HEC121120 (2 μM) treatment resulted in suppression of HBV DNA, HBsAg and HBeAg while entecavir (ETV) had no effect on either viral antigen. HEC121120 is a novel class I CAM, which demonstrated improved antiviral properties both in vitro and in vivo, further clinical study will be conducted to evaluate the antiviral potency in CHB patients.
- JNJ-73763989 / J&J, bersacapavir (JNJ-56136379) / J&J
Understanding the dynamics of HBsAg decline through model-informed drug development (MIDD) of JNJ-3989 and JNJ-6379 for the treatment of chronic hepatitis B virus infection (CHB) (Poster Area) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1729;
HBsAg levels decreased in a dosedependent manner up to 48 weeks of JNJ-3989 treatment in REEF-1. Covariate analysis identified that HBsAg dynamics display treatmentand subgroup-specific behavior.
- ZM-H1505R / Zhimeng Biopharma
Safety, tolerability, pharmacokinetics, and preliminary antiviral activity of the capsid assembly modulator (CAM) ZM-H1505R after multiple escalatiing oral dosed in patients with chronic hepatitis B virus (CHB) Infection (Poster Area) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1726;
It produced a substantial decrease in HBV-DNA and HBV pgRNA levels in the serum of CHB patients. On the basis of these results, ZM-H1505R was recommended for further evaluation in phase II trials.
- ALG-000184 / Aligos Therap
Safety, pharmacokinetics, and antiviral activity of the class II capsid assembly modulator ALG-000184 in subjects with chronic hepatitis B (Poster Area) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1724;
On the basis of these results, ZM-H1505R was recommended for further evaluation in phase II trials. All dose levels of ALG-000184 were well tolerated, exhibited predictable PK, and resulted in similar, substantial antiviral activity in untreated CHB subjects, regardless of HBeAg status.
- GST-HG141 / Fujian Cosunter
GST-HG141 inhibits de novo HBV cccDNA formation in cultured primary human hepatocytes (Poster Area) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1718;
It acts on different steps of the HBV life cycle, suggesting dual/multiple mechanisms of antiviral action. Further development of GST-HG141 for chronic HBV infections is warranted.
- 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 (Capital Suite 2) - Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_626;
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.
- || Review, Journal: How to interpret viral markers in the management of chronic hepatitis B infection. (Pubmed Central) - Mar 16, 2022
Further studies should expand the current evidence on the use of markers in relation to antiviral agents currently under evaluation. Wide availability of these markers in regions with a high incidence of HBV infection is of paramount importance.
- | Journal: Disassembly of Single Virus Capsids Monitored in Real Time with Multicycle Resistive-Pulse Sensing. (Pubmed Central) - Mar 12, 2022
In all cases, disassembly was an accelerating process, where capsids catastrophically disassembled within a few 100 ms of reaching critical stability; disassembly rates reached tens of dimers per second just before capsids fell apart. Some disassembly events exhibited metastable intermediates that appeared to lose one or more trimers of dimers in a stepwise fashion.
- | Journal: N6-methyladenosine modification of the 5' epsilon structure of the HBV pregenome RNA regulates its encapsidation by the viral core protein. (Pubmed Central) - Mar 11, 2022
HBV polymerase interaction with 5' epsilon was independent of mA modification of 5' epsilon. This study highlights yet another pivotal role of mA modification in dictating the key events of the HBV life cycle and provides avenues for investigating RNA-protein interactions in various biological processes, including viral RNA genome encapsidation in the context of mA modification.