Modified Cyclic Dinucleotide Compounds for STING Activation
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Solution Overview
Problem
Current cyclic dinucleotide compounds are limited in their ability to effectively activate STING for cytokine production across different human STING alleles, requiring higher doses and potentially leading to side effects due to insufficient binding affinity and stability.
Innovation Solution
Development of modified cyclic dinucleotide compounds with a 3',5'-linked locked nucleic acid and a 2'-monofluorinated 3',5'-linked nucleotide, both comprising a purine nucleobase and a phosphorothioate moiety, which exhibit enhanced binding affinity to human STING and improved cellular activity, allowing for lower effective doses and increased stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cyclic dinucleotide compounds are used to activate STING, then cytokine production is induced, but higher doses are required due to insufficient binding affinity and stability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of cyclic dinucleotide compounds through multiple substitutions: replacing oxygen with sulfur in phosphodiester bonds to form phosphorothioate bonds, adding fluorine atoms at specific positions (2'-monofluorinated), and incorporating locked nucleic acid (LNA) moieties. These structural parameter changes enhance binding affinity to STING, allowing effective activation at lower doses while maintaining reliability.
Solution Approach 2:
The invention creates composite molecular structures by combining multiple modified nucleotide components: LNA (locked nucleic acid) units with ribose-like sugar but constrained conformation, 2'-monofluorinated nucleotides with enhanced metabolic stability, and phosphorothioate linkages. This composite approach integrates the beneficial properties of each modification to achieve superior binding affinity and stability compared to unmodified CDNs.
2Reliability
If current cyclic dinucleotide compounds are used to activate STING, then cytokine production is induced, but side effects increase due to insufficient binding affinity requiring higher doses
Solution Approach 1:
By changing the chemical parameters of the CDN compounds through phosphorothioate substitution, fluorine incorporation, and LNA integration, the patent achieves higher binding affinity to STING. This enhanced affinity allows selective activation of the desired immune response pathway at lower concentrations, reducing off-target effects and side effects that would occur with higher doses of less effective compounds.
Solution Approach 2:
The modified CDN compounds act as improved intermediaries that selectively mediate the interaction between the immune system and STING. The structural modifications enhance the specificity and efficiency of this mediation, allowing effective immune activation without the need for high concentrations that would cause harmful side effects.
3Reliability
If current cyclic dinucleotide compounds are used, then STING activation occurs, but stability is reduced leading to lower cellular activity
Solution Approach 1:
The patent changes the chemical composition parameters by incorporating 2'-monofluorinated nucleotides and phosphorothioate bonds, which are known to enhance nucleotide stability against enzymatic degradation. These parameter changes result in modified CDNs with improved metabolic stability and prolonged cellular activity while maintaining reliable STING activation.
Data Source
AI summary
Compounds of formula (I) wherein Base1 and Base2 are defined as in claim 1 are modulators of STING.