Enhanced stability of a chimeric hepatitis B core antigen virus-like-particle (HBcAg-VLP) by a C-terminal linker-hexahistidine-peptide

Virus-like-particles (VLPs) are attractive nanoparticulate scaffolds for broad applications in material/biological sciences and medicine. Prior their functionalization, specific adaptations have to be carried out. These adjustments frequently lead to disordered particles, but the particle integrity...

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Published in:	Journal of nanobiotechnology Vol. 16; no. 1; p. 39
Main Authors:	Schumacher, Jens, Bacic, Tijana, Staritzbichler, René, Daneschdar, Matin, Klamp, Thorsten, Arnold, Philipp, Jägle, Sabrina, Türeci, Özlem, Markl, Jürgen, Sahin, Ugur
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 13-04-2018 BioMed Central BMC
Subjects:	B cells Bionanoparticles Capsid and particle stability Chimeric VLP Computational biology Hepatitis B Hepatitis B Core Antigens - isolation & purification Hepatitis B Core Antigens - metabolism Histidine Histidine - metabolism Models, Molecular Molecular mechanism Nanoparticles Oligopeptides - metabolism Quality Control Recombinant Proteins - isolation & purification Recombinant Proteins - metabolism Risk factors Stress, Physiological Structural biology Thyroid hormones Virion - metabolism Virion - ultrastructure Bioengineering Virus-like-particles (VLP) Molecular mechanism Vaccine Hepatitis B virus Chimeric VLP Capsid and particle stability Structural biology Bionanoparticles Computational biology
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Summary:	Virus-like-particles (VLPs) are attractive nanoparticulate scaffolds for broad applications in material/biological sciences and medicine. Prior their functionalization, specific adaptations have to be carried out. These adjustments frequently lead to disordered particles, but the particle integrity is an essential factor for the VLP suitability. Therefore, major requirements for particle stabilization exist. The objective of this study was to evaluate novel stabilizing elements for functionalized chimeric hepatitis B virus core antigen virus-like particles (HBcAg-VLP), with beneficial characteristics for vaccine development, imaging or delivery. The effects of a carboxy-terminal polyhistidine-peptide and an intradimer disulfide-bridge on the stability of preclinically approved chimeric HBcAg-VLPs were assessed. We purified recombinant chimeric HBcAg-VLPs bearing different modified C-termini and compared their physical and chemical particle stability by quantitative protein-biochemical and biophysical techniques. We observed lower chemical resistance of T = 3- compared to T = 4-VLP (triangulation number) capsids and profound impairment of accessibility of hexahistidine-peptides in assembled VLPs. Histidines attached to the C-terminus were associated with superior mechanical and/or chemical particle stability depending on the number of histidine moieties. A molecular modeling approach based on cryo-electron microscopy and biolayer interferometry revealed the underlying structural mechanism for the strengthening of the integrity of VLPs. Interactions triggering capsid stabilization occur on a highly conserved residue on the basis of HBcAg-monomers as well as on hexahistidine-peptides of adjacent monomers. This new stabilization mechanism appears to mimic an evolutionary conserved stabilization concept for hepadnavirus core proteins. These findings establish the genetically simply transferable C-terminal polyhistidine-peptide as a general stabilizing element for chimeric HBcAg-VLPs to increase their suitability.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1477-3155 1477-3155
DOI:	10.1186/s12951-018-0363-0