Capsid assembly mod 
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  • ||||||||||  Journal:  Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability. (Pubmed Central) -  Jul 22, 2024   
    Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.
  • ||||||||||  Review, Journal:  Chemical approaches to probe and engineer AAV vectors. (Pubmed Central) -  Jul 9, 2024   
    Unlike genetic strategies, which can be more disruptive to the delicate capsid assembly and packaging processes, "late-stage" chemical modification of the assembled capsid-whether at natural amino acid residues or site-specifically installed noncanonical amino acid residues-often enables a versatile approach to introducing new properties to the capsid. This review summarizes the significant recent progress in AAV capsid engineering strategies, with a particular focus on chemical modifications in advancing the next generation of AAV-based gene therapies.
  • ||||||||||  Journal:  A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex. (Pubmed Central) -  Jun 19, 2024   
    An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
  • ||||||||||  Journal:  Stimulus-responsive assembly of nonviral nucleocapsids. (Pubmed Central) -  Apr 28, 2024   
    Analyses by transmission and cryo-electron microscopy confirmed that the resulting assemblies are structurally identical to their RNA-containing counterparts produced in vivo. Enzymatically triggered cage formation broadens the range of RNA molecules that can be encapsulated by NC-4, provides unique opportunities to study the co-assembly of capsid and cargo, and could be useful for studying other nonviral and viral assemblies.
  • ||||||||||  Journal:  Limits of economy and fidelity for programmable assembly of size-controlled triply periodic polyhedra. (Pubmed Central) -  Apr 26, 2024   
    Off-target misassembly occurs via incorporation of a variant of disclination defects, generalized to the case of hyperbolic crystals. The possibility of these topological defects is a direct consequence of the very same symmetry principles that underlie the economical design, exposing a basic tradeoff between design economy and fidelity of programmable, size controlled assembly.
  • ||||||||||  Journal:  Structural morphing in the viral portal vertex of bacteriophage lambda. (Pubmed Central) -  Apr 25, 2024   
    Our research focused on examining the structures of the portal vertex in both its preliminary prohead state and the fully mature virion state of bacteriophage lambda. By analyzing these structures, we were able to understand how the portal protein undergoes conformational changes during maturation, the mechanism by which it prevents DNA from escaping, and the process of DNA spirally gliding.
  • ||||||||||  Journal:  Biophysics-Guided Lead Discovery of HBV Capsid Assembly Modifiers. (Pubmed Central) -  Apr 15, 2024   
    The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.
  • ||||||||||  Journal:  Identification of clickable HIV-1 capsid-targeting probes for viral replication inhibition. (Pubmed Central) -  Mar 27, 2024   
    One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell-based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV-1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV-1 replication.
  • ||||||||||  Review, Journal:  Toward a Functional Cure for Hepatitis B. (Pubmed Central) -  Mar 27, 2024   
    These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.
  • ||||||||||  Preclinical, Journal:  Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation. (Pubmed Central) -  Mar 20, 2024   
    To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure.IMPORTANCETreatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.
  • ||||||||||  HBV RNA  () -  Mar 5, 2024 - Abstract #APASL2024APASL_2986;    
    The value of HBV RNA to predict virological relapse after stopping nucleos(t)ide analog is controversial, but detectable HBV RNA is found to associate with an increased risk of hepatitis flare. With the development of new therapeutics for chronic hepatitis B, HBV RNA can be a biomarker for target engagement particularly for capsid assembly inhibitors.
  • ||||||||||  Journal:  SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction. (Pubmed Central) -  Feb 21, 2024   
    Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle.
  • ||||||||||  Journal:  Synthesis of the full-length hepatitis B virus core protein and its capsid formation. (Pubmed Central) -  Feb 15, 2024   
    Sequential ligations using four peptide segments enabled the synthesis of Cp183 via convergent and C-to-N direction approaches. After refolding under appropriate conditions, followed by the addition of nucleic acid, the synthetic Cp183 assembled into capsid-like particles.
  • ||||||||||  ALG-000184 / Aligos Therap
    Alg-000184  (Room 04, E) -  Jan 6, 2024 - Abstract #APASL2024APASL_2154;    
    Dosing of untreated HBeAg+ CHB subjects with 100 mg ALG-000184 + ETV x ?24 weeks was well tolerated and had greater antiviral effects compared with ETV alone. Substantial declines in HBV DNA/RNA and antigens have been observed in untreated HBeAg+ CHB subjects receiving 300 mg ALG- 000184
  • ||||||||||  Novel Markers of Hepatitis B: Clinical Utility for New Treatment Strategies () -  Jan 2, 2024 - Abstract #CROI2024CROI_60;    
    These investigational biomarkers are now used for the evaluation of target engagement and antiviral efficacy to assist the development of new antivirals (Capsid Assembly Modulators, SiRNA, antisense oligonucleotides, etc.) and immunomodulatory agents (check point inhibitors, TLR agonists, therapeutic vaccines, etc.). Altogether, these non-invasive viral markers show promise for a deep phenotyping of patients and show potential for patient stratification and novel treatment evaluation.
  • ||||||||||  Sunlenca (lenacapavir) / Gilead
    Virion Maturation: Folding Into the Right Shape () -  Jan 2, 2024 - Abstract #CROI2024CROI_56;    
    Lenacapavir (LEN, Gilead Sciences) is the first-in-class capsid targeting, long-acting and highly potent antiretroviral...The ability of LEN to offset the delicate balance between pentamers and hexamers resulted in formation of defective or atypical assemblies of CA both in vitro and in virions. These findings provide a new insight into molecular mechanisms of action of LEN.
  • ||||||||||  Review, Journal:  Recent Advances in the Development of Sulfamoyl-Based Hepatitis B Virus Nucleocapsid Assembly Modulators. (Pubmed Central) -  Dec 27, 2023   
    Additionally, we explore newly identified sulfamoyl-based CAMs, including sulfamoyl bicyclic carboxamides, sulfamoyl aromatic heterocyclic carboxamides, sulfamoyl aliphatic heterocyclic carboxamides, cyclic sulfonamides, and non-carboxamide sulfomoyl-based CAMs. We believe that certain molecules derived from sulfamoyl groups have the potential to be developed into essential components of a well-suited combination therapy, ultimately yielding superior clinical efficacy outcomes in the future.
  • ||||||||||  Preclinical, Journal:  Novel non-HAP class A HBV capsid assembly modulators have distinct in vitro and in vivo profiles. (Pubmed Central) -  Dec 25, 2023   
    These so-called non-HAP CAM-As have intriguing properties in cell culture but also clear virus-infected cells from the mouse liver in a gradual and sustained way. We believe they represent a considerable improvement over previously reported molecules and may one day be part of curative treatment combinations for chronic hepatitis B.
  • ||||||||||  Journal:  Architecture of the baculovirus nucleocapsid revealed by cryo-EM. (Pubmed Central) -  Nov 23, 2023   
    In the base, these proteins interact with a 7-fold symmetric capsid plug, while a portal-like structure is seen in the central portion of head. Additionally, we propose an application of AlphaFold2 for model building in intermediate resolution density.
  • ||||||||||  lamivudine HBV / Generic mfg.
    Journal:  Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability. (Pubmed Central) -  Nov 17, 2023   
    The results from biological evaluation demonstrated that compound 6a-25 (EC = 0.020 ?M) exhibited greater potency than the positive drug lamivudine (EC = 0.09 ?M), and was comparable to the lead compound GLS4 (EC = 0.007 ?M)...Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 ?g mL; pH 7.0: 6.85 ?g mL; pH 7.4: 25.48 ?g mL), liver microsomal metabolic stability (t = 108.2 min), and lower hERG toxicity (10 ?M inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.
  • ||||||||||  Journal:  Molecular architecture of Salmonella typhimurium virus P22 genome ejection machinery. (Pubmed Central) -  Nov 12, 2023   
    Cryo-EM analysis of P22 mutants lacking the ejection proteins gp7 or gp20 and biochemical analysis of purified recombinant proteins suggest that gp7 and gp20 form a molecular complex associated with the tail apparatus via the portal protein barrel. We identified a putative signal transduction pathway from the tailspike to the tail needle, mediated by three flexible loops in the tail hub, that explains how lipopolysaccharide (LPS) is sufficient to trigger the ejection of the P22 DNA in vitro.
  • ||||||||||  Arc mediates a novel form of intercellular long-term depression (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_11344;    
    Arc that is transferred in EVs induces synaptic depression in neighboring dendrites. We propose that neurons incorporated into the memory "engram" that undergo LTP release Arc to increase the "signal-to-noise" of memory circuits by weakening synapses on neurons not active during memory encoding.