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- | 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.
- | Journal: Structure-Based Discovery of N-Sulfonylpiperidine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication. (Pubmed Central) - Mar 11, 2022
In summary, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.
- || Review, Journal: Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives. (Pubmed Central) - Mar 11, 2022
Moreover, several CAMs have entered clinical development. The aim of this review is to summarize the mechanism of action (MoA) and the advancements in the clinical development of CAMs and in the characterization of their mod of action.
- | Journal: Targeting Chikungunya Virus Entry: alternatives for new inhibitors in drug discovery. (Pubmed Central) - Mar 3, 2022
Based on this, Phe118, Val179, and Lys181 were found to be the most frequent residues, being present in 89.6, 82.7, and 93.1% of complexes, respectively. Lastly, some chemical aspects associated with interactions of these inhibitors and mature envelope E3-E2-E1 glycoproteins' complex were discussed to provide data for scientists worldwide, supporting their search for new inhibitors against this emerging arbovirus.
- | vebicorvir (ABI-H0731) / Assembly Biosci, morphothiadine mesilate (GLS4) / HEC Pharm, bersacapavir (JNJ-56136379) / J&J
Journal: An automated microfluidic platform for the screening and characterization of novel hepatitis B virus capsid assembly modulators. (Pubmed Central) - Mar 3, 2022
With this proof-of-concept study, we believe that this microfluidic system is a robust primary screening tool for HBV CAM drug discovery, especially for the hit finding and hit-to-lead optimization phases. In addition to EC values, this system gives valuable first information about the mode of action of novel CAM screening compounds.
- | AB-506 / Arbutus
Preclinical, Journal: Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein. (Pubmed Central) - Feb 25, 2022
In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.
- | Journal: VP39 of Spodoptera litura multicapsid nucleopolyhedrovirus cannot efficiently rescue the nucleocapsid assembly of vp39-null Autographa californica multiple nucleopolyhedrovirus. (Pubmed Central) - Feb 23, 2022
AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B. Altogether, our results demonstrated that VP39 from SpltMNPV cannot efficiently substitute AcMNPV VP39 during nucleocapsid assembly in AcMNPV.
- | Journal: Core Protein-Directed Antivirals and Importin β Can Synergistically Disrupt HBV Capsids. (Pubmed Central) - Feb 19, 2022
We show that these molecules can, synergistically with importins, disrupt capsids. This mechanism of action, synergism with host protein, has potential to disrupt the virus lifecycle and activate the innate immune system.
- | Journal: Structural Basis of Human Parainfluenza Virus 3 Unassembled Nucleoprotein in Complex with Its Viral ChaperoneHPIV3 Nucleoprotein-Phosphoprotein Structure. (Pubmed Central) - Feb 19, 2022
We obtained a high-affinity P-derived peptide inhibitor, specifically targeted N and greatly interfered with the binding of the N to RNA, thereby inhibiting viral encapsidation and replication. In summary, our results provide new insights into the paramyxovirus genome replication and nucleocapsid assembly, and lay the basis for drug development.
- | Journal: 4-oxooctahydroquinoline-1(2H)-carboxamides as Hepatitis B Virus (HBV) Capsid Core Protein Assembly Modulators. (Pubmed Central) - Feb 17, 2022
A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.
- | Preclinical, Journal: Production and application of mouse monoclonal antibodies targeting linear epitopes in pB602L of African swine fever virus. (Pubmed Central) - Feb 17, 2022
The results showed that pB602L was detectable with all three mAbs in immunohistochemical staining, but only B2H10 was suitable for detecting the proteins in ASFV-infected PAMs by IFA. In summary, we developed eight anti-pB602L mouse mAbs recognizing three linear epitopes in the protein, which can be used as reagents for basic and applied research on ASFV.
- || Clinical, Review, Journal: Current Progress in the Development of Hepatitis B Virus Capsid Assembly Modulators: Chemical Structure, Mode-of-Action and Efficacy. (Pubmed Central) - Feb 12, 2022
As followers of the early CAMs, the therapeutic efficacy of several non-classical CAMs has been evaluated in humanized mouse models of HBV infection. It is expected that these next-generation HBV CAMs will be promising candidates for a series of extended human clinical trials.
- || Review, Journal: The Ins and Outs of Herpesviral Capsids: Divergent Structures and Assembly Mechanisms across the Three Subfamilies. (Pubmed Central) - Feb 8, 2022
Furthermore, capsid assembly studies have suggested subfamily-specific roles of viral capsid protein homologs. In this review, we compare capsid structures, assembly mechanisms, and capsid protein functions across human herpesvirus subfamilies, highlighting the differences.
- || Review, Journal: Chronic hepatitis B: New potential therapeutic drugs target. (Pubmed Central) - Feb 5, 2022
This review will explore the up-to-date advances in the development of new direct-acting anti-HBV drugs. Hopefully, with the combination of the current antiviral drugs and the newly developed direct-acting antiviral drugs targeting the different steps of the HBV life cycle, the ultimate eradication of CHB infection will soon be achieved.
- | Journal: The Role of Tape Measure Protein in Nucleocytoplasmic Large DNA Virus Capsid Assembly. (Pubmed Central) - Feb 3, 2022
In this study, we focused on the critical roles that TmP plays in the assembly of icosahedral NCLDV capsids, answering a question raised in a previously proposed spiral mechanism. Interestingly, basic local alignment search on the TmPs showed no significant hits in poxviruses, which might be the factor that differentiates poxviruses and icosahedral NCLDVs in their morphogenesis.
- || Review, Journal: The remarkable viral portal vertex: structure and a plausible model for mechanism. (Pubmed Central) - Feb 2, 2022
Recent high-resolution in situ structures reveal various conformational states of the portal and the asymmetric interactions between the 12-fold portal and the fivefold capsid. These lead to a valve-like mechanism for this symmetry-mismatched portal vertex that regulates DNA flow through the channel, a critical function for high fidelity assembly of an infectious virion.
- | 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.