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Assessing sequence plasticity of a virus-like nanoparticle by evolution toward a versatile scaffold for vaccines and drug delivery. | LitMetric

Assessing sequence plasticity of a virus-like nanoparticle by evolution toward a versatile scaffold for vaccines and drug delivery.

Proc Natl Acad Sci U S A

Department of Chemical Engineering, Stanford University, Stanford, CA 94305; Department of Bioengineering, Stanford University, Stanford, CA 94305

Published: October 2015

AI Article Synopsis

  • - Virus-like particles (VLPs) are being studied for uses in biotechnology, including vaccines and drug delivery, but challenges like instability and immunogenicity limit their development.
  • - The research utilizes a cell-free protein synthesis method to create and test HBc protein variants, aiming to enhance VLP stability through artificial disulfide bonds and alterations to surface charges.
  • - A modified HBc VLP showed minimal immunogenicity in mice, indicating potential for medical use and introducing a new approach to understanding viral protein structures and developing viral therapeutics.

Article Abstract

Virus-like particles (VLPs) have been extensively explored as nanoparticle vehicles for many applications in biotechnology (e.g., vaccines, drug delivery, imaging agents, biocatalysts). However, amino acid sequence plasticity relative to subunit expression and nanoparticle assembly has not been explored. Whereas the hepatitis B core protein (HBc) VLP appears to be the most promising model for fundamental and applied studies; particle instability, antigen fusion limitations, and intrinsic immunogenicity have limited its development. Here, we apply Escherichia coli-based cell-free protein synthesis (CFPS) to rapidly produce and screen HBc protein variants that still self-assemble into VLPs. To improve nanoparticle stability, artificial covalent disulfide bridges were introduced throughout the VLP. Negative charges on the HBc VLP surface were then reduced to improve surface conjugation. However, removal of surface negative charges caused low subunit solubility and poor VLP assembly. Solubility and assembly as well as surface conjugation were greatly improved by transplanting a rare spike region onto the common shell structure. The newly stabilized and extensively modified HBc VLP had almost no immunogenicity in mice, demonstrating great promise for medical applications. This study introduces a general paradigm for functional improvement of complex protein assemblies such as VLPs. This is the first study, to our knowledge, to systematically explore the sequence plasticity of viral capsids as an approach to defining structure function relationships for viral capsid proteins. Our observations on the unexpected importance of the HBc spike tip charged state may also suggest new mechanistic routes toward viral therapeutics that block capsid assembly.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603490PMC
http://dx.doi.org/10.1073/pnas.1510533112DOI Listing

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