- |||||||||| Zolgensma (onasemnogene abeparvovec-xioi) / Novartis, Roctavian (valoctocogene roxaparvovec) / BioMarin, Luxturna (voretigene neparvovec-rzyl) / Novartis, Roche
Development of Stabilized AAV Capsids for Vector Engineering (Concourse Hall 150 & 151) - May 3, 2023 - Abstract #ASGCT2023ASGCT_2094; Adeno-associated virus (AAV) vectors are promising candidates for gene therapy, as illustrated by the recent FDA or EMA approvals of Luxturna, Zolgensma and Valoctocogene Roxaparvovec...To determine whether AAV9 capsids bearing a combination of these mutations had increased mutational tolerance, we generated peptide-modified capsid libraries within AAV9 or a highly stabilized capsid variant and screened these libraries for production fitness. This work informs the development of novel AAV capsids with increased mutational tolerance for AAV engineering.
- |||||||||| Modifying Immune Responses to Adeno-Associated Virus (AAV) Vectors by Capsid Engineering (Concourse Hall 152 & 153) - May 3, 2023 - Abstract #ASGCT2023ASGCT_2056;
Beyond that, humoral responses against AAV capsids measured by anti-AAV2 IgG2a antibodies were mitigated and delayed in AAV2.MB-injected mice independent of the route of administration. To conclude, by incorporating an immune-modulatory peptide into the AAV2 capsid we could modify the activation of innate as well as adaptive immunity in response to AAV2 vectors.
- |||||||||| ALG-000184 / Aligos Therap
Treatment for up to 24 weeks with the capsid assembly modulator ALG-000184 results in dose related reductions in HBsAg in subjects with HBeAg positive chronic hepatitis B (Poster Area) - Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_2076; P1 Importantly, dosing with ALG-000184 plus ETV resulted in dose-dependent, clinically relevant declines in HBsAg, suggesting a potential role of ALG-000184 in combination regimens for functional cure. Figure: Table: Mean BL and change from BL in HBV DNA and HBsAg with ALG-000184 plus ETV or ETV alone HBV DNA HBsAg ALG-000184 100 mg + ETV ALG-000184 300 mg +ETV ETV ALG-000184 100 mg + ETV ALG-000184 300 mg +ETV ETV BL, mean (SEM) 8.6 (0.1) N=8 8.2 (0.3) N=11 8.1 (0.3) N=6 4.7 (0.1) N=8 4.4 (0.2) N=11 4.3 (0.1) N=6 CFB, mean (SEM) - 6.4 (0.2) Week 24 N=4 - 5.4 (0.3) Week 16 N=6 - 3.8 (0.3) Week 12 N=3 - 0.5 (0.1) Week 24 N=4 - 0.5 (0.2) Week 16 N=6 +0.05 (0.02) Week 12 N=3 BL= baseline.
- |||||||||| Journal: What will it take to cure hepatitis B? (Pubmed Central) - Mar 28, 2023
Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.
- |||||||||| Journal: HIV-1 is dependent on its immature lattice to recruit IP6 for mature capsid assembly. (Pubmed Central) - Mar 21, 2023
IP6 cannot be replaced by other inositol phosphate (IP) molecules, as substitution with other IPs profoundly slows mature assembly kinetics and results in virions with gross morphological defects. Our results demonstrate that while HIV-1 can become independent of IP6 for immature assembly, it remains dependent upon the metabolite for mature capsid formation.
- |||||||||| Combination therapies for chronic HBV and HDV (Strauss 2-3) - Mar 18, 2023 - Abstract #EASLILC2023EASL_ILC_207;
Furthermore, different combinations of treatments, such as capsid assembly modulators, RNA checkpoint inhibitors will be discussed. For hepatitis delta both the options of curative and suppressive therapy will be shown.
- |||||||||| Journal: Simultaneous membrane and RNA binding by Tick-Borne Encephalitis Virus capsid protein. (Pubmed Central) - Mar 2, 2023
We confirm the biological relevance of the biophysical findings by using mass spectrometry to show that purified virions contain negatively-charged lipids. Our results suggest that nucleocapsid assembly is coordinated by negatively-charged membrane patches on the endoplasmic reticulum and that the capsid protein mediates direct contacts between the nucleocapsid and the membrane.
- |||||||||| Journal: Assembly and Capsid Expansion Mechanism of Bacteriophage P22 Revealed by High-Resolution Cryo-EM Structures. (Pubmed Central) - Mar 1, 2023
The amino acid interactions between gp5 and gp8 in the procapsid were consistent with the results of previous biochemical studies involving mutant proteins. Our structures reveal hydrogen bonds and salt bridges between the gp5 subunits in the procapsid and the conformational changes of the gp5 domains involved in the closure of the local sixfold opening and a thinner capsid shell during capsid maturation.
- |||||||||| Review, Journal: Let's phase it: viruses are master architects of biomolecular condensates. (Pubmed Central) - Feb 27, 2023
Herein, we discuss how RNA viruses establish replication organelles and nucleocapsid assembly sites, and the evidence that these compartments form through phase separation. While this review focuses on RNA viruses, accumulating evidence suggests that all viruses rely on phase separation and form biomolecular condensates important for completing the infectious cycle.
- |||||||||| Journal: Development of Enterovirus anti-viral agents that target the viral 2C protein. (Pubmed Central) - Feb 15, 2023
The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.
- |||||||||| Single-particle measurements with integrated in-plane nanofluidic devices (Indiana Ballroom E (Indianapolis Marriott Downtown)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_10332;
To improve temporal response, reactions are coupled directly with the particle-size measurements. With these integrated nanofluidic devices, we can probe assembly and disassembly processes over a range of reaction conditions.
- |||||||||| Journal: African swine fever virus transmembrane protein pEP84R guides core assembly. (Pubmed Central) - Jan 31, 2023
Altogether, these results indicate that pEP84R plays a crucial role in core assembly by targeting the core shell polyproteins to the inner viral envelope, which enables subsequent genome packaging and nucleoid formation. These findings unveil a key regulatory mechanism for ASFV morphogenesis and identify a relevant novel target for the development of therapeutic tools against this re-emerging threat.
- |||||||||| Journal: Critical mechanistic features of HIV-1 viral capsid assembly. (Pubmed Central) - Jan 7, 2023
We show that IP6, in small quantities at first, promotes curvature generation by trapping pentameric defects in the growing lattice and shifts assembly behavior toward kinetically favored outcomes. Our analysis also suggests that IP6 can stabilize metastable capsid intermediates and can induce structural pleomorphism in mature capsids.
- |||||||||| Journal: Optimization of non-equilibrium self-assembly protocols using Markov state models. (Pubmed Central) - Jan 1, 2023
We demonstrate our approach with two examples; a simple semi-analytic model for the folding of a polymer of colloidal particles, and a more complex model for capsid assembly. Our results show that optimizing time-dependent protocols can achieve significant improvements in the yields of selected structures, including equilibrium free energy minima, long-lived metastable structures, and transient states.
- |||||||||| HBV Life Cycle and Main Targets of Direct and Indirect Viral Therapies (2F Room 201DEF) - Dec 18, 2022 - Abstract #APASL2023APASL_110;
CHB leads to exhaustion of antiviral adaptive immunity, so indirect antiviral approaches to stimulate pattern recognition receptors for enhancing innate immunity or restore exhausted T cell immunity by targeting immune checkpoint molecules are also being explored. To summarize, direct and indirect antiviral agents are being developed and some of them show promising results and will pave the way toward HBV cure.
- |||||||||| Vemlidy (tenofovir alafenamide) / Gilead
Journal: Characterization of a Novel Capsid Assembly Modulator for the Treatment of Chronic Hepatitis B Virus Infection. (Pubmed Central) - Dec 16, 2022 In addition, GS-SBA-1 demonstrated in vitro additivity in combination with tenofovir alafenamide (TAF)...Furthermore, GS-SBA-1 prevents the production of extracellular HBV RNA-containing viral particles in vitro. Collectively, these data demonstrate that GS-SBA-1 is a potent CAM that has the potential to enhance viral suppression in combination with an NA.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Regulation of Epstein-Barr Virus Minor Capsid Protein BORF1 by TRIM5α. (Pubmed Central) - Dec 12, 2022 However, chloroquine treatment restores the stability of BORF1(6KR), suggesting that TRIM5α destabilizes BORF1 via direct recognition of its substrate for autophagic degradation. These results reveal novel insights into the antiviral impact of TRIM5α beyond retroviruses.
- |||||||||| Journal: A finely tuned interplay between calcium binding, ionic strength and pH modulates conformational and oligomerization equilibria in the Respiratory Syncytial Virus Matrix (M) protein. (Pubmed Central) - Nov 10, 2022
Furthermore, the dissociation constants estimated for the low- and high affinity calcium binding sites are 13 μM and 58 nM, respectively, suggesting an intracellular calcium sensing mechanism of RSV-M upon infection. We uncover a finely tuned interplay between calcium binding, ionic strength, and pH changes compatible with the different cellular compartments where M plays key roles, uncovering diverse conformational equilibria, oligomerization, and high order structures, required to stabilize the virion particle by a layer of molecules positioned between the membrane and the nucleocapsid.
- |||||||||| Journal: Design, synthesis, and biological evaluation of novel sulfamoylbenzamide derivatives as HBV capsid assembly modulators. (Pubmed Central) - Nov 9, 2022
Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure-activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs.
- |||||||||| Journal: Near-atomic, non-icosahedrally averaged structure of giant virus Paramecium bursaria chlorella virus 1. (Pubmed Central) - Nov 6, 2022
These variants create varied capsid microenvironments for the associations of fibers, a vesicle, and previously unresolved minor capsid proteins. Our structure reveals the identities and atomic models of the capsid components that do not obey the overall icosahedral symmetry and leads to a model for how these components are assembled and initiate capsid assembly, and this model might be applicable to many other giant viruses.
- |||||||||| Hepcludex (bulevirtide) / Gilead
Journal: State-of-the-art and emerging antivirals for chronic hepatitis B infection. (Pubmed Central) - Nov 5, 2022 Classes of antivirals include entry inhibitors (bulevirtide), capsid assembly modulators (CAMs), translation inhibitors [small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs)] and HBsAg secretion inhibitors [nucleic acid polymers (NAPs)]...Combinations of agents of different classes are starting to be evaluated. Continued efforts are required in order to address many unanswered questions about the optimal combined regimens of finite duration which will be safe and well tolerated achieving functional cure in a substantial proportion of chronic HBV patients.
|