Stabilized Coronavirus Spike Protein for Prefusion Antigen Design
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Solution Overview
Problem
There is a need for stabilized coronavirus S proteins that can be used for identifying drug candidates and stimulating an effective immune response to the S protein, as the sequence and structure of the SARS-CoV-2 spike protein are known but not effectively utilized in existing technologies.
Innovation Solution
Engineered coronavirus S proteins with specific mutations, such as disulfide bonds, cavity filling substitutions, electrostatic or polar interactions, and proline substitutions, are developed to stabilize the protein and enhance its functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the native coronavirus S protein is used, then it can bind to host cellular receptor ACE2, but it exhibits dynamic conformation during membrane fusion and low immunogenicity
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (e.g., N-proline substitutions at positions 983, 984, 985, 986, 987, 988; C-disulfide bonds between positions 983-988 and 1058-1063) that alter the physical-chemical parameters of the S protein, stabilizing it in a prefusion conformation while preserving ACE2 binding capability
Solution Approach 2:
The patent creates a composite structure by combining multiple stabilization elements (N-terminal proline substitutions, C-terminal disulfide bonds, and electrostatic interactions) within the S protein framework, forming a composite stabilized protein that maintains both structural integrity and biological function
2Reliability
If the native coronavirus S protein is used, then it can bind to host cellular receptor ACE2, but it exhibits low immunogenicity
Solution Approach 1:
The patent modifies the immunogenicity parameter by stabilizing the S protein in a prefusion conformation through amino acid substitutions, which enhances the presentation of immunodominant epitopes and improves the immune response while maintaining ACE2 binding function
Solution Approach 2:
The patent applies preliminary action by pre-stabilizing the S protein in its prefusion conformation before immune system exposure, ensuring that the most immunogenic conformation is presented to antibodies and T cells, thereby enhancing immunogenicity before any conformational changes occur
3Stability of the object's composition
If stabilization mutations are introduced to improve stability and immunogenicity, then the protein can be used in vaccine formulation, but the sequence complexity increases
Solution Approach 1:
The patent applies local quality by introducing stabilization mutations only at specific localized regions (N-terminal positions 983-988 and C-terminal positions involving disulfide bonds) rather than throughout the entire S protein sequence, thereby achieving global stability improvement with minimal local sequence changes
Data Source
AI summary
Provided herein are engineered Coronavirus S proteins, such as engineered SARS-CoV-2 S proteins. In some aspects, the engineered S proteins exhibit enhanced conformational stability and/or antigenicity. Methods are also provided for use of engineered proteins as diagnostics, in screening platforms and/or in vaccine compositions.