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Engineering Metastability into a Virus-like Particle to Enable Triggered Dissociation
Caleb A Starr1, Smita Nair1, Sheng-Yuan Huang2
1Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405, United States.
Journal of the American Chemical Society
|January 18, 2023
Summary
Researchers engineered a hepatitis B virus (HBV) virus-like particle (VLP) delivery system. This triggered VLP disassembly using chemical biology, enabling controlled cargo release for therapeutic applications.
Area of Science:
- Biochemistry
- Chemical Biology
- Materials Science
Background:
- Virus-like particles (VLPs) are promising for drug delivery but require triggered cargo release mechanisms.
- Hepatitis B virus (HBV) capsid protein (Cp) self-assembles into VLPs, offering a potential platform for development.
Purpose of the Study:
- To engineer a chemically triggered disassembly mechanism for HBV VLPs.
- To create a metastable VLP system that releases cargo in response to specific environmental cues.
Main Methods:
- Redesigned HBV Cp with two cysteines (C150, C124) for crosslinking and chemical modification.
- Assembled 120-dimer VLPs and induced metastability using a fluorophore at C124.
- Utilized FRET, size exclusion chromatography, and resistive-pulse sensing to monitor VLP dissociation.
- Employed mathematical modeling to understand disassembly kinetics and nucleation processes.
Main Results:
- Engineered Cp150-V124C VLPs spontaneously crosslinked and formed a metastable state upon reaction with maleimidyl BoDIPY-FL.
- VLPs dissociated in the presence of reducing agents, confirmed by biophysical techniques.
- Dissociation exhibited a lag phase, consistent with a nucleation-dependent mechanism predicted by mathematical modeling.
- Similar triggered dissociation was observed in VLPs transfected into hepatoma cells.
Conclusions:
- A generalizable chemical biology strategy was developed to create environmentally responsive VLPs.
- This approach enables controlled cargo release from VLPs, enhancing their potential as therapeutic delivery platforms.
- The engineered HBV VLP system demonstrates tunable disassembly for targeted drug delivery applications.
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