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- || Review, Journal: Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs-First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor. (Pubmed Central) - Aug 14, 2021
This chemotype potently blocks HIV-1 replication in T cells by specifically inhibiting immature HIV-1 capsid assembly but fails to select for resistant viral variants over 37 passages, suggesting a host protein target. Development of such small molecules could yield novel host-targeting antiretroviral drugs and provide insight into chronic diseases resulting from dysregulation of host machinery targeted by these drugs.
- [VIRTUAL] Revealing the mechanisms of viral capsid assembly using computational approaches (Room: Zoom Room 09) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_7189;
Formulas generated for the total number of each binding mode within one capsid show the mode within trisymmetron are dominating the stabilization of the capsid which is consistent to previous observation. Besides the viral capsid assembly, methods introduced in this study can be applied to study more complicated assembly process for other biomolecular structures.
- [VIRTUAL] Modifying self-assembly of 2D viral capsid-like structures via inter-particle potential variation (Room: Virtual Room) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_3396;
We see distinct shifts in the window of capsid formation compared to the system with fixed and homogeneous inter-particle attractions. Our results provide insights on how dynamic inter-particle interactions can alter the window of self-assembly.
- [VIRTUAL] HPV virus-like particle formation conserves key structural elements to ensure assembly across types (Room: Virtual Room) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_3372;
These conserved structures play an important role in enabling both capsid assembly as well as drive the formation of inter-capsomere disulfide bonds that provide long-term stability for the capsid. Finally, we analyze Cryo-EM structures of other types and demonstrate high conservation of these important 3D structural motifs across structures, even where sequence conservation is not maintained, suggesting synthetic targets that could promote the high-fidelity assembly of VLPs across types.
- Approaches for mining natural products databases for ribonucleocapsid assembly inhibitors (Room: Hall B4) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_2277;
In the initial studies, we report that the highest-ranking compounds bind to the RNA binding site of N protein. This approach seems feasible for the identification of lead compounds in the discovery of inhibitors that target a crucial step in the life cycle of zoonotic RNA viruses.
- | Preclinical, Journal: Capsid assembly is regulated by amino acid residues asparagine 47 and 48 in the VP2 protein of porcine parvovirus. (Pubmed Central) - Aug 7, 2021
Site-directed mutation at 48Asn did not affect the ability of monomers to form into oligomers, but destroyed the ability of oligomers to assemble into macromolecular particles, influencing both capsid assembly and HA activity. Our findings provide valuable information on the mechanisms of PPV capsid assembly and the possibility of chimeric VLP vaccine development by replacing the first 47 amino acids at the N-terminal of the VP2 protein.
- || morphothiadine mesilate (GLS4) / HEC Pharm
Clinical, PK/PD data, Journal: Antiviral Activity and Pharmacokinetics of the HBV Capsid Assembly Modulator GLS4 in Patients with Chronic HBV Infection. (Pubmed Central) - Aug 5, 2021
Our findings provide valuable information on the mechanisms of PPV capsid assembly and the possibility of chimeric VLP vaccine development by replacing the first 47 amino acids at the N-terminal of the VP2 protein. Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.
- | Journal: Evolving ribonucleocapsid assembly/packaging signals in the genomes of the human and animal coronaviruses: targeting, transmission and evolution. (Pubmed Central) - Aug 3, 2021
We also found that many motifs were highly conserved in both characters and positioning on the genomes throughout the lineages that make them promising therapeutic targets. The mechanisms of encapsidation can affect the recombination and co-infection as well.Communicated by Ramaswamy H. Sarma.
- | Journal: Dynamics of the SARS-CoV-2 nucleoprotein N-terminal domain triggers RNA duplex destabilization. (Pubmed Central) - Jul 28, 2021
Based on experimental information available in the literature, we constructed kinetics models for N-NTD-mediated dsRNA melting. Our results support a 1:1 stoichiometry (N-NTD:dsRNA), matching MD simulations and raising different possibilities for N-NTD action: (i) two N-NTD arms of dimeric N would bind to two different RNA sites, either closely or spatially spaced in the viral genome, in a cooperative manner; (ii) monomeric N-NTD would be active, opening up the possibility of a regulatory dissociation event.
- | Journal: Asymmetric reconstruction of mammalian reovirus reveals interactions among RNA, transcriptional factor µ2 and capsid proteins. (Pubmed Central) - Jul 23, 2021
Polymerase complexes in three Spinoreovirinae subfamily members are organized with different pseudo-D symmetries to engage their highly diversified genomes. The above interactions and those between symmetry-mismatched receptor-binding σ1 trimers and RNA-capping λ2 pentamers balance competing needs of capsid assembly, external protein removal, and allosteric triggering of endogenous RNA transcription, before, during and after infection, respectively.
- | Journal: Effect of mutations in capsid shell protein on the assembly of BmCPV virus-like particles. (Pubmed Central) - Jul 18, 2021
Still, the simultaneous mutation of the three sites had a significant impact. The experimental results demonstrate that the SPD of CSP plays an essential role in assembly of the viral capsid, which lays the foundation for further analysis of the molecular and structural mechanism of BmCPV capsid assembly.
- || Review, Journal: Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B. (Pubmed Central) - Jul 14, 2021
This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."
- || Clinical, Review, Journal: Foot-and-mouth disease virus: prospects for using knowledge of virus biology to improve control of this continuing global threat. (Pubmed Central) - Jul 9, 2021
These vaccines, despite certain shortcomings, have been used very successfully (e.g. in Europe) to control the disease but it still remains endemic in much of Africa, southern Asia and the Middle East. Hence there remains a significant risk of reintroduction of the disease into highly susceptible animal populations with enormous economic consequences.
- [VIRTUAL] All-Atom MD simulations of the HBV capsid: Revealing mechanisms of function and disruption. () - Jun 27, 2021 - Abstract #ACSMARM2021ACS_MARM_191;
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 subdomains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.
- | JNJ-56136379 / J&J
Preclinical, Journal: Anti-HBV activity of the HBV capsid assembly modulator JNJ-56136379 across full-length genotype A-H clinical isolates and core site-directed mutants in vitro. (Pubmed Central) - Jun 26, 2021
JNJ-56136379, a potent HBV CAM-N, currently in Phase 2 clinical development, was generally fully active against an extensive panel of genotype A-H clinical isolates, regardless of the presence of nucleos(t)ide analogue resistance or BCP/PC mutations. JNJ-56136379 activity was reduced by some core amino acid substitutions in the CAM-binding pocket.
- | Journal: A lysine ring in HIV capsid pores coordinates IP6 to drive mature capsid assembly. (Pubmed Central) - Jun 24, 2021
Finally, in single molecule TIRF microscopy experiments, capsid lattices in permeabilised K25 mutant virions are rapidly lost and cannot be stabilised by IP6. These results suggest that the coordination of IP6 by a second charged ring in mature hexamers drives the assembly of conical capsids capable of reverse transcription and infection.
- | Journal: Pharmacophore Model and Atom-Based 3D Quantitative Structure activity Relationship (QSAR) of Human Immunodeficiency Virus-1 (HIV-1) Capsid Assembly Inhibitors. (Pubmed Central) - Jun 22, 2021
Hypothesis also showed a leave-n-out cross validation for training set (R, 0.928). Interestingly, the predicted activity of true test set compounds was found in the close vicinity of their experimental activity suggesting the methodology used and models generated can be applied to identify potential new chemical entities with better HIV-1 capsid assembly inhibition.
- | Preclinical, Journal: Changes in membrane dielectric properties of porcine kidney cells provide insight into the antiviral activity of glycine. (Pubmed Central) - Jun 22, 2021
These results suggest that DEP can be used to non-invasively monitor the viral infection cycle as well as screen antiviral compounds. DEP can augment traditional tools by elucidating membrane polarization changes due to drug mechanisms that interrupt the virus infection cycle.
- || RG7907 / Roche
Clinical, P1 data, PK/PD data, Journal: A five-in-one first-in-human study to assess safety, tolerability, and pharmacokinetics of RO7049389, an inhibitor of hepatitis B virus capsid assembly, after single and multiple ascending doses in healthy participants. (Pubmed Central) - Jun 22, 2021
P1
No effect on QT interval was observed up to a single dose of 2500 mg. RO7049389 displayed a favorable safety, tolerability and PK profile suitable for further clinical development.
- | Journal: Engineering a Virus-like Particle to Display Peptide Insertions Using an Apparent Fitness Landscape. (Pubmed Central) - Jun 22, 2021
This library generates a discrete map of three amino acid insertions permitted at this location, validates the FG loop as a valuable position for peptide insertion, and illuminates how properties such as charge, flexibility, and hydrogen bonding can interact to preserve or disrupt capsid assembly. Taken together, the results highlight the potential to engineer VLPs in a systematic manner, paving the way to exploring the applications of peptide insertions in biomedically relevant settings.
- | Journal: The trimeric major capsid protein of Mavirus is stabilized by its interlocked N-termini enabling core flexibility for capsid assembly. (Pubmed Central) - Jun 22, 2021
Assessing the role of the N-terminal arm in maintaining capsomer stability showed that its detachment is required for capsomer dissociation, constituting a barrier towards capsomer monomerisation. Surprisingly, capsomer dissociation was irreversible since it was followed by a global structural rearrangement of the protomers as indicated by computational studies showing a rearrangement of the N-terminus blocking part of the capsomer forming interface.
- | tenofovir disoproxil fumarate / Generic mfg.
Journal: Discovery of Novel Pyrimidine-Based Capsid Assembly Modulators as Potent Anti-HBV Agents. (Pubmed Central) - Jun 22, 2021
One of the synthesized derivatives, compound 23h (R = MeSO, R = 1-piperidin-4-amine, R = 3-Cl-4-F-aniline) displayed potent inhibitory effects in the in vitro assays (52% inhibition in the protein-based assay at 100 nM and an IC value of 181 nM in the serum HBV DNA quantification assay). Moreover, treatment with compound 23h for 5 weeks significantly decreased serum levels of HBV DNA levels (3.35 log reduction) in a human liver-chimeric uPA/SCID mouse model, and these effects were significantly increased when 23h was combined with tenofovir, a nucleotide analogue inhibitor of reverse transcriptase used for the treatment of HBV infection.
- || Review, Journal, IO biomarker: Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. (Pubmed Central) - Jun 22, 2021
Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
- | Journal: Structural phylogenetic analysis reveals lineage-specific RNA repetitive structural motifs in all coronaviruses and associated variations in SARS-CoV-2. (Pubmed Central) - Jun 22, 2021
However, multiple sequence alignment reveals that the majority of SARS-CoV-2 possesses a variant RSM harboring SL5b C241U, and intriguingly, several variations in the coding sequences of viral proteins, such as Nsp12 P323L, S protein D614G, and N protein R203K-G204R, are concurrently found with such variant RSM. In conclusion, the comprehensive exploration for RSMs reveals phylogenetic insights into the RNA structural elements in CoVs as a whole and provides a new perspective on variations currently found in SARS-CoV-2.
- | Journal: Regulation of HBV Replication by Cyclin Docking Motifs in Core Protein. (Pubmed Central) - Jun 16, 2021
Mutations of these docking sites reduced capsid protein phosphorylation, impaired CDK2 packaging into HBV capsids, and blocked HBV infection. These results provide novel insights regarding CDK2 packaging into HBV capsids and the role of CDK2 in HBV infection and should facilitate the development of antiviral drugs that target the HBV capsid protein.
- || Mavyret (glecaprevir/pibrentasvir) / AbbVie, Enanta Pharma
Clinical, Review, Journal: Breakthroughs and challenges in the management of pediatric viral hepatitis. (Pubmed Central) - Jun 8, 2021
Anti-HBV investigational compounds are reviewed in light of the pathophysiology in the pediatric population, including capsid assembly modulators, antigen secretion inhibitors, silencing RNAs, and immune modifiers. Recommendations for screening and management of immunosuppressed children or those with other risk factors or comorbidities are also summarized.
- || Review, Journal: Structure, dynamics and phase separation of measles virus RNA replication machinery. (Pubmed Central) - Jun 4, 2021
Here, we review recent progress in this direction, covering the dynamics of the nucleocapsid assembly process, high resolution structure and dynamics of protein:RNA interactions, and the investigation of the role of intrinsic conformational disorder in pre-assembly nucleoprotein/phosphoprotein complexes. Finally, we discuss the role of viral factories in the form of phase-separated membraneless organelles formed by measles virus phospho and nucleoproteins that promote the assembly of nucleocapsid structures.
- || Review, Journal: Recent Advances in Hepatitis B Treatment. (Pubmed Central) - Jun 3, 2021
Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.
- | Journal: An Engineered Maturation Cleavage Provides a Recombinant Mimic of Foot-and-Mouth Disease Virus Capsid Assembly-Disassembly. (Pubmed Central) - Jun 3, 2021
The reactivity with anti-VP4 antibodies was reduced for the 12S pentamers, consistent with the predicted loss of VP4. Reactivity with other antibodies was similar for both pentamers suggesting that major antigenic features may be preserved between the VP4 containing assembly pentamers and the disassembly pentamers lacking VP4.
- [VIRTUAL] Investigating A Novel Phage Packaging Interference Mechanism By A Subfamily Of Staphylococcal Phage Satellites (Poster Hall) - May 31, 2021 - Abstract #WMF2021WMF_5561;
As the protein sequences of Rcp and CpmAB are unrelated, this strategy represents a fascinating example of convergent evolution. This result, moreover, indicates that the production of SaPI-sized particles is a widespread strategy of phage interference conserved during SaPI evolution.
- | Journal: AcMNPV PKIP is required for hyperexpression of very late genes and involved in the hyperphosphorylation of the viral basic protein P6.9. (Pubmed Central) - May 29, 2021
Further experiments showed that PKIP interacted with P6.9 during virus infection, and the deletion of pkip resulted in decreased hyperphosphorylation of P6.9. Taken together, our results indicated that PKIP is involved in hyperphosphorylation of P6.9, which in return maybe required for hyperexpression of very late genes.
- | Journal: Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity. (Pubmed Central) - May 15, 2021
Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC > 10 µM) than NVR3-778 (CC, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.
- | Journal: Assembly of Capsids from Hepatitis B Virus Core Protein Progresses through Highly Populated Intermediates in Presence and Absence of RNA. (Pubmed Central) - May 15, 2021
Comparisons between truncated and full-length HBV capsid proteins reveal that the unstructured C-terminal domain has a significant impact on the assembly process, and is required to obtain a more complete mechanistic understanding of HBV capsid formation. These results also illustrate how combining scattering information from different time-points during time-resolved experiments can be utilized to derive a structural model of protein self-assembly pathways.
- | Journal: Nonsymmetrical Dynamics of the HBV Capsid Assembly and Disassembly Evidenced by Their Transient Species. (Pubmed Central) - May 15, 2021
On the one hand, our findings confirm and extend previous views as to the hysteresis phenomena observed and theorized in capsid formation and dissociation. On the other hand, they uncover specifics that may directly relate to the functions of HBV subunits in the viral cycle.
- | Journal: Parameterization of a drug molecule with a halogen σ-hole particle using ffTK: Implementation, testing, and comparison. (Pubmed Central) - May 14, 2021
Our results indicate that parameterization with the LP particle significantly improves the accuracy of the electrostatic response of the molecule, especially around the halogen atom. Although the inclusion of the LP particle does not produce a prominent effect on the interactions between the molecule and its target protein, the protein-ligand binding performance is greatly improved by optimization of the parameters.
- | Journal: Dynamics of Hepatitis B virus capsid protein dimer regulate assembly through an allosteric network. (Pubmed Central) - May 7, 2021
The differences in dynamics when comparing HBV and human Cp149-Y132A as well as the differences in dynamics when comparing the HBV and WHV Cps allowed us to map an allosteric network within the HBV dimer. Through a careful comparison of structure, stability and dynamics using four different capsid protein dimers, we conclude that protein subunit dynamics regulate HBV capsid assembly.
- [VIRTUAL] AAV Capsid Proteins Fused with SARS-CoV-2 RBD or RBM: Expression in E. coli, In-Vitro Assembly, and Characterization () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_735;
Unexpectedly, the domain VP3_RBD VLPs induced a low level of RBD-specific antibodies, but an intermediate level of VP3 VLP antibodies. Taken together our data suggest that in vitro AAV VLPs bear potential as vaccine scaffolds and that AAV VLP production using E. coli lends itself as a versatile strategy for vaccines and drug delivery.
- [VIRTUAL] The Nucleolar-Enriched Deubiquitinating Enzyme USP36 Regulates AAP Ubiquitination () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_291;
We found that FLAG-USP36 pulled down HA-AAP2, providing evidence that USP36 and AAP2 can interact in HEK293 cells. To our knowledge, this is the first study of regulation of post-translational modifications on AAP by cellular proteins and how the regulation relates to the AAP stability.
- [VIRTUAL] Disorder in the C-terminus of VP Dictates AAP Requirement for AAV Capsid Assembly () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_288;
Conversely, VPs with reduced flexibility at the 2-fold or 5-fold axis do not autonomously oligomerize and are more prone to degradation, necessitating non-VP factors for promoting VP oligomerization via the 2-fold or 5-fold axis; and therefore, they are dependent on AAP for VP oligomerization and subsequent capsid assembly. Taken together, our data suggest that enhanced disorder in the C-terminus of VP that promotes structural flexibility in the 2-fold and 5-fold axis regions plays a critical role in conferring the ability to undergo AAP-independent capsid assembly.
- [VIRTUAL] AAV Capsid Property Estimation Is Improved by Combining Single-Molecule ID Tags and Hierarchical Bayesian Modeling of Experimental Processes () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_190;
The resulting model learns the effect of mutations on capsid properties by integrating information from multiple variants, which may be necessary when measurements are noisy. Overall, our approach can be simply incorporated into many barcode-based assays of capsid function and significantly improves estimation of packaging and transduction in large, barcoded AAV libraries.
- [VIRTUAL] Co-Identification and Characterization of Host and Viral Protein Interactomes during AAV Production by Two Different Proximity Labeling Methods () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_120;
Our findings may shed some lights to developing strategies to improve vector empty/full particle ratios and virus genome titer. *Co-corresponding authors.
- || Clinical, Journal: Local stabilization of subunit-subunit contacts causes global destabilization of Hepatitis B virus capsids. (Pubmed Central) - Apr 27, 2021
Using cryo-electron microscopy we observed that DBT1 led to asymmetric capsids where well-defined DBT1 density was bound at all inter-subunit contacts. These results suggest that DBT1 can support assembly by increasing buried surface area but induce disassembly of metastable capsids by favoring asymmetry to induce structural defects.
- || Review, Journal: Discovery and optimization of benzenesulfonamides-based hepatitis B virus capsid modulators via contemporary medicinal chemistry strategies. (Pubmed Central) - Apr 20, 2021
Sulfonamides are synthetic functional groups, found in several drugs. Herein, we provide a concise report focusing on the sulfamoylbenzamides as HBV capsid modulators, and medicinal chemistry strategies used in their design and development.
- | Journal: Rapidly Forming Early Intermediate Structures Dictate the Pathway of Capsid Assembly. (Pubmed Central) - Apr 16, 2021
In all cases, intermediates between 35 and 90 subunits did not accumulate. These results are consistent with the presence of low barrier paths that connect early and late intermediates and direct the ultimate assembly path to late intermediates where assembly can be paused.
- | Journal: Berberine Chloride is an Alphavirus Inhibitor That Targets Nucleocapsid Assembly. (Pubmed Central) - Apr 10, 2021
BBC acted on a late step in the alphavirus exit pathway, namely the formation of the nucleocapsid containing the infectious viral RNA. Better understanding of nucleocapsid formation and its inhibition by BBC will provide important information on the mechanisms of infectious alphavirus production and may enable their future targeting in antiviral strategies.
- GST-HG141 / Fujian Cosunter
[VIRTUAL] GST-HG141, a novel clinical-stage hepatitis B virus capsid assembly modulator (Poster area) - Apr 9, 2021 - Abstract #EASLILC2021EASL_ILC_1155;
It accelerates HBV capsid assembly in vitro, leading to formation of “empty” capsids, devoided of genetic material. However, its mode of action and resistance profile appear to be distinct from other class I CAMs in development.
- VNRX-9945 / VenatoRx
[VIRTUAL] Discovery and preclinical profile of VNRX-9945, a potent, broadly active core protein inhibitor for the treatment of hepatitis B virus (HBV) infection (Poster area) - Apr 9, 2021 - Abstract #EASLILC2021EASL_ILC_1154;
The antiviral, pharmacokinetic and safety profile supports the inclusion of VNRX-9945 in future combination therapies that are optimized to achieve a functional cure for chronic HBV. VNRX-9945 is being advanced rapidly into clinical development as a potential best- in-class core protein inhibitor.
- ALG-000286 / Aligos Therap, ALG-000111 / Aligos Therap
[VIRTUAL] Capsid assembly modulator ALG-000111 and its prodrug ALG-000286 display excellent in vitro and in vivo antiviral activity (Poster area) - Apr 9, 2021 - Abstract #EASLILC2021EASL_ILC_1145;
VNRX-9945 is being advanced rapidly into clinical development as a potential best- in-class core protein inhibitor. With sub-nanomolar activity and deep knockdown of HBV DNA in cell-based assays and the AAV-HBV mouse model, ALG- 000286 is a promising Class II CAM candidate for further development.
- ALG-125755 / Aligos Therap, ALG-020572 / Aligos Therap
[VIRTUAL] Combination drug interactions of hepatitis B virus ( HBV) small interfering RNA (siRNA) and antisense oligonucleotides (ASO) in vitro and in vivo (Poster area) - Apr 9, 2021 - Abstract #EASLILC2021EASL_ILC_1097;
The HBV siRNA, ALG-125755, in combination with the ASO, ALG-020572, demonstrated additive to minor synergy in vitro and in vivo. Further investigation of the strategy to combine HBV siRNA and ASO compounds in CHB clinical trials is warranted.
- | JNJ-56136379 / J&J
Journal: Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379. (Pubmed Central) - Apr 7, 2021
Collectively, these data demonstrate that JNJ-6379 has a dual MOA on the early and late steps of the HBV life cycle, which is different to the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment, and may translate into higher HBV functional cure rates.