Capsid Protein Heterodimers for Asymmetric Virus-Like Particle Assembly
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Solution Overview
Problem
Existing methods for controlling the assembly pathway of symmetrical viral capsids are limited, preventing the incorporation of specific asymmetric features and conditional stops for information insertion and cargo loading, which hinders the development of advanced applications.
Innovation Solution
The creation of orthohepadnavirus capsid protein heterodimers, composed of non-identical half-dimers that spontaneously dimerize without a peptide linker, allows for controlled assembly and formation of mosaic virus-like particles with distinct patches, enabling hierarchical assembly and loading of nucleic acids, polypeptides, or small molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If symmetrical viral capsids are used as nanotechnology platforms, then structural simplicity and ease of manufacture are improved, but control over assembly pathways and ability to incorporate asymmetric features deteriorate
Solution Approach 1:
The capsid protein is divided into two distinct half-dimers (first half-dimer and second half-dimer) that can independently fold and then spontaneously associate. This segmentation allows each half-dimer to be engineered with specific functions or modifications while maintaining the overall capsid structure, enabling controlled assembly pathways and asymmetric feature incorporation.
Solution Approach 2:
The invention introduces asymmetry by using non-identical first and second half-dimers to form heterodimers. This asymmetric design allows different regions of the capsid to have distinct properties, enabling conditional stops for information insertion and cargo loading, and providing control over assembly pathways that symmetrical designs cannot achieve.
2Device complexity
If symmetrical subunits are used to assemble capsids, then structural simplicity is improved, but opportunity to control reaction and incorporate specific asymmetric features deteriorates
Solution Approach 1:
By segmenting the capsid protein into separable first and second half-dimers, the invention maintains structural simplicity through spontaneous self-assembly while creating opportunities for asymmetric feature incorporation. Each half-dimer can be independently engineered with specific modifications, epitopes, or functional domains.
Solution Approach 2:
The invention applies local quality by allowing different half-dimers to have different properties or modifications at specific locations within the capsid structure. This enables site-specific incorporation of asymmetric features, cargo loading regions, or functional elements without compromising the overall structural integrity.
3Adaptability or versatility
If capsids require conditional stops for information insertion and cargo loading, then application versatility is improved, but assembly control mechanisms deteriorate
Solution Approach 1:
The invention implements preliminary action by pre-engineering the first and second half-dimers with specific properties, modifications, or functional elements before assembly. This allows conditional stops and cargo loading sites to be built into the structure during the design phase, eliminating the need for complex post-assembly modification mechanisms.
Solution Approach 2:
The heterodimeric capsid system provides self-service through spontaneous self-assembly of the first and second half-dimers into functional capsid structures. The system automatically creates the necessary assembly control mechanisms through the inherent properties of the engineered half-dimers, without requiring external control systems or complex machinery.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the formation of addressable capsid structures that can be modified and loaded with specific contents, expanding the applications of viral capsids in drug delivery, diagnostics, and targeted therapies.
Implementation Method 1
wherein the first half-dimer and the second half-dimer spontaneously dimerize with one another
Data Source
AI summary
Embodiments described herein provide orthohepadnavirus capsid protein (Cp) heterodimers, bicistronic vectors encoding the heterodimers, and methods for producing the heterodimers. The heterodimers can be used to form mosaic virus-like particles. In certain embodiments, the heterodimers can form a hexamer, which in turn can be used to nucleate capsid formation, resulting in a Janus particle-like virus-like particle. The hexamer's can then be removed, leaving holey capsids. The capsids can be loaded with, for example, one or more polypeptides, small molecules, or a combination of polypeptides and small molecules. The holes of the holey capsids can be filled with another orthohepadnavirus heterodimer or a homodimer.