Peptide Mimics for HLA Binding Without Post-Translational Modification
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Solution Overview
Problem
Current methods for producing MHC class II peptide complexes and mRNA vaccines for autoimmune disease treatment face challenges due to the need for post-translational modification of amino acids, which is not feasible with existing synthesis techniques, particularly for rheumatoid arthritis (RA) therapies.
Innovation Solution
Development of synthetic peptide mimics that substitute citrulline with another amino acid, such as glutamine, to bind to the peptide-binding groove of HLA-DR0401 and recognized by T cells derived from T cells that are activated in RA patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If post-translational modification is performed to create citrullinated peptides for MHC class II binding, then the peptide can bind to HLA molecules and be recognized by T cells, but the manufacturing process becomes complex and time-consuming
Solution Approach 1:
The patent incorporates citrulline residues directly into the peptide sequence during synthesis, performing the modification in advance rather than requiring post-translational modification. This preliminary incorporation of the modified amino acid simplifies the manufacturing process while ensuring the peptide maintains its ability to bind HLA molecules and be recognized by T cells.
Solution Approach 2:
The patent creates synthetic peptide copies that mimic the structure and function of naturally occurring citrullinated peptides. These synthetic analogs replicate the key citrulline residues necessary for HLA binding and T cell recognition, providing a simplified manufacturing alternative to producing authentic post-translationally modified peptides.
2Reliability
If mRNA vaccines are used for tolerization, then antigen-specific tolerance can be induced, but post-translational modification of amino acids cannot be achieved
Solution Approach 1:
The patent designs mRNA sequences that encode synthetic peptide variants containing citrulline residues. These mRNA-based synthetic peptides copy the essential structural features and citrulline modifications of natural autoantigens, enabling the vaccine to induce antigen-specific tolerance while bypassing the limitation of mRNA systems unable to perform post-translational modifications.
Solution Approach 2:
The patent modifies the amino acid sequence parameters by incorporating citrulline residues at specific positions within the peptide encoded by the mRNA. This parameter change in the primary sequence allows the synthetic peptide to maintain HLA binding capability and T cell recognition while being producible through mRNA translation without requiring post-translational modification machinery.
Data Source
AI summary
The present invention relates to mimics of post-translationally modified naturally occurring peptides, wherein said peptide mimics bind to a peptide-binding groove of human leukocyte antigen (HLA) molecules to the same extent as the naturally occurring post-translationally modified peptide, wherein said peptide mimics are recognized by T cells to the same extent as the naturally occurring post-translationally modified peptide, and additionally wherein said peptide mimics have a three-dimensional structure substantially identical to said post-translationally modified naturally occurring peptide. Such peptide mimics can be used alone of bound to a carrier, and have utility inter alia in methods for the treatment, alleviation and prevention of autoimmune diseases, and as components in tolerogenic vaccines.