Deuterated Polyribonucleotides for Low-Immunogenic Protein Expression
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Solution Overview
Problem
Existing polyribonucleotides used for protein synthesis in therapeutic contexts face challenges with significant immunogenicity and insufficient protein expression levels.
Innovation Solution
The use of deuterated adenosine, cytidine, guanosine, and uridine nucleotides in polyribonucleotides to reduce immunogenicity and enhance protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If polyribonucleotides are used for protein synthesis in therapeutic contexts, then protein expression can be optimized, but immunogenicity increases and stability decreases
Solution Approach 1:
The patent applies parameter changes by substituting hydrogen atoms with deuterium atoms in the nucleotide structure. This isotopic substitution modifies the physical and chemical parameters of the polyribonucleotide, specifically reducing immunogenicity while maintaining or enhancing protein expression capability. The deuterated nucleotides change the mass and bonding characteristics of the RNA molecule, thereby altering its interaction with the immune system.
Solution Approach 2:
The patent creates a composite structure by combining deuterated and non-deuterated nucleotides within the polyribonucleotide sequence. This composite approach allows optimization of specific regions of the RNA molecule, where deuterated nucleotides are placed at positions that reduce immunogenicity while non-deuterated nucleotides maintain coding function and stability.
2Productivity
If polyribonucleotides are used for protein synthesis in therapeutic contexts, then protein expression can be optimized, but stability decreases
Solution Approach 1:
The deuterium substitution changes the vibrational frequency and bond strength of the nucleotide components. The C-D and N-D bonds formed upon deuterium incorporation are stronger and have lower zero-point energy compared to C-H and N-H bonds, thereby increasing the thermal and chemical stability of the polyribonucleotide structure while preserving its ability to direct protein synthesis.
3Object-affected harmful factors
If modified nucleotides are used to reduce immunogenicity, then immunogenicity decreases, but manufacturing complexity increases
Solution Approach 1:
The patent employs parameter changes through isotopic substitution, which is achieved by cultivating host cells in deuterated media during the production phase. This approach modifies the nucleotide composition parameter without requiring complex post-synthesis chemical modification steps, thereby reducing manufacturing complexity compared to other nucleotide modification strategies.
Data Source
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AI summary
The present disclosure provides polyribonucleotides, in particular polyribonucleotides, which comprise deuterated adenosine, cytidine, guanosine, and/or uridine residues and which show reduced immunogenicity and/or enhanced expression, and methods of using such polyribonucleotides for the therapy of diseases.