Stabilized Pre-fusion RSV F Proteins via Mutations
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Solution Overview
Problem
Current vaccines against respiratory syncytial virus (RSV) are ineffective due to the instability of the pre-fusion conformation of the RSV F protein, which makes it difficult to produce stable pre-fusion RSV F proteins suitable for vaccination.
Innovation Solution
Stabilization of the pre-fusion RSV F proteins through specific mutations, such as N67I, S215P, T357K, and N371Y, combined with a heterologous trimerization domain, to maintain the protein in the pre-fusion conformation, along with the use of nucleic acid molecules and vectors to induce an immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pre-fusion RSV F proteins are used for vaccination, then neutralizing antibodies and protective immunity are induced, but the pre-fusion conformation is unstable and refolds to post-fusion conformation
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (N67I, S215P, T357K, N371Y) at defined positions in the RSV F protein sequence. These mutations alter the physical-chemical parameters of the protein structure, specifically stabilizing the pre-fusion conformation through changes in hydrophobic interactions, hydrogen bonding, and steric constraints at critical regions including the fusion peptide and heptad repeat domains.
Solution Approach 2:
The patent creates a composite protein structure by combining the RSV F protein with a heterologous trimerization domain (such as T4 fibritin or Fc region). This composite construction enforces a stable trimeric pre-fusion conformation that resists refolding, effectively combining the immunogenicity of the RSV F protein with the structural stability of the heterologous domain.
2Ease of manufacture
If pre-fusion RSV F proteins are produced for vaccine development, then effective vaccine candidates are obtained, but production is difficult due to conformational instability
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (N67I, S215P, T357K, N371Y) at defined positions in the RSV F protein sequence. These mutations alter the physical-chemical parameters of the protein structure, specifically stabilizing the pre-fusion conformation through changes in hydrophobic interactions, hydrogen bonding, and steric constraints at critical regions including the fusion peptide and heptad repeat domains.
Solution Approach 2:
The patent creates a composite protein structure by combining the RSV F protein with a heterologous trimerization domain (such as T4 fibritin or Fc region). This composite construction enforces a stable trimeric pre-fusion conformation that resists refolding, effectively combining the immunogenicity of the RSV F protein with the structural stability of the heterologous domain.
3Reliability
If RSV F protein refolds from pre-fusion to post-fusion conformation, then fusion function is achieved, but vaccine efficacy is reduced due to loss of pre-fusion specific epitopes
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (N67I, S215P, T357K, N371Y) at defined positions in the RSV F protein sequence. These mutations alter the physical-chemical parameters of the protein structure, specifically stabilizing the pre-fusion conformation through changes in hydrophobic interactions, hydrogen bonding, and steric constraints at critical regions including the fusion peptide and heptad repeat domains.
Solution Approach 2:
The patent creates a composite protein structure by combining the RSV F protein with a heterologous trimerization domain (such as T4 fibritin or Fc region). This composite construction enforces a stable trimeric pre-fusion conformation that resists refolding, effectively combining the immunogenicity of the RSV F protein with the structural stability of the heterologous domain.
Data Source
AI summary
Stable pre-fusion respiratory syncytial virus (RSV) F proteins, immunogenic compositions including the proteins and uses thereof for the prevention and/or treatment of RSV infection are described.