Modified Cytidine Nucleosides for Low-Immune High-Expression mRNA
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Solution Overview
Problem
Existing mRNA drugs face limitations due to immune responses and reduced protein production when incorporating naturally occurring nucleotide modifications, necessitating novel nucleosides and nucleic acids to enhance therapeutic efficacy.
Innovation Solution
Development of modified nucleosides and nucleotides, such as 4-guanidinocytidine, through specific synthetic methods, including protection and deprotection steps, to minimize immune response and improve protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally occurring nucleotide modifications are incorporated into mRNA, then the mRNA can be synthesized from basic ribonucleotides, but immune response is elicited and protein production is limited
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides at specific positions (R1, R2, R4, R5 groups) to create non-naturally occurring modified nucleosides. These structural parameter changes allow the mRNA to maintain stability and protein production capability while avoiding immune recognition, thus resolving the contradiction between therapeutic benefit and immune response
Solution Approach 2:
The patent creates synthetic analogs that copy the essential functional properties of naturally occurring modified nucleotides (such as m5C, m4C) while using different chemical structures. These copied functions are achieved through the modified nucleoside framework where various substituent groups replicate the stabilizing and translational effects without triggering immune responses
2Reliability
If naturally occurring nucleotide modifications are incorporated into mRNA, then the mRNA can be synthesized from basic ribonucleotides, but protein production is limited
Solution Approach 1:
By changing the chemical parameters of the nucleoside structure (introducing various R groups at positions 1, 2, 4, and 5), the patent creates modified nucleosides that enhance mRNA stability and translation efficiency. These parameter changes directly improve protein production efficiency while maintaining the ability to be synthesized from basic ribonucleotides
Solution Approach 2:
The patent employs composite chemical structures by combining the core nucleoside framework with various substituent groups (alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl groups). This composite approach creates nucleosides with optimized properties for both synthesis from basic ribonucleotides and enhanced protein production capability
Data Source
AI summary
Disclosed are a modified cytidine compound, i.e. a new derivative cytidine generated by adding a guanidyl at position 4 of a cytidine, and a nucleic acid containing the modified compound, for example, RNA. The nucleic acid containing the modified cytidine, especially mRNA, can significantly increase the expression quantity of the mRNA in vivo.