Cyclic Di-Nucleotide STING Agonists for Interferon Induction
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Solution Overview
Problem
There is a need for new agents that can induce potent type I interferon production, which is crucial for anti-viral and anti-cancer therapies, as existing compounds have limitations in activating the cGAS-STING pathway effectively.
Innovation Solution
Development of novel cyclic di-nucleotide compounds with specific structural formulas that act as STING agonists, capable of inducing interferon production by activating the STING pathway, including various structural modifications and pharmaceutical compositions for enhanced efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used to activate the cGAS-STING pathway, then some immune response is generated, but the type I interferon production is insufficient and lacks potency
Solution Approach 1:
The patent employs parameter changes by systematically modifying the chemical structure of cyclic di-nucleotide compounds, specifically varying the ribose 2'-position substituents (R groups) to optimize STING binding affinity and interferon induction potency. Different R group configurations (e.g., 2'-O-Me, 2'-F, 2'-Cl) are tested to achieve enhanced biological activity while maintaining structural stability
Solution Approach 2:
The patent applies local quality by introducing specific functional groups at particular positions of the cyclic di-nucleotide structure. The 2'-position of the ribose ring is specifically modified with different substituents to create localized improvements in STING interaction, while the rest of the molecular structure remains relatively conserved to maintain overall structural integrity
2Reliability
If cyclic di-nucleotide compounds with specific structural modifications are developed, then STING-dependent type I interferon production is enhanced, but the structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the cyclic di-nucleotide structure into distinct functional domains: the core cyclic backbone that maintains structural stability, and the variable 2'-position substituents that provide the necessary complexity for enhanced STING binding. This modular approach allows systematic optimization of potency while managing molecular complexity
Solution Approach 2:
The patent achieves universality by designing a core cyclic di-nucleotide structure that can accommodate multiple different 2'-position substituents, creating a platform that generates multiple active compounds with varying potencies. This multi-functional approach allows a single structural framework to serve multiple therapeutic purposes through systematic substitution
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds effectively induce STING-dependent type I interferon and cytokine production, potentially enhancing anti-viral and anti-tumor immune responses, offering a new approach in therapeutic applications.
Implementation Method 1
cGAS catalyzes the generation of the cyclic-dinucleotide 2'-3' cGAMP
Implementation Method 2
A conformational change is undergone by cGAMP-bound STING, which translocates to a perinuclear compartment
Implementation Method 3
type I interferons can rapidly engage their cognate receptors and trigger the activation of interferon-responsive genes
Data Source
AI summary
A class of polycyclic compounds of general formula (I), of general formula (I′), or of general formula (I″), wherein Base1, Base2, Y, Ya, Xa, Xa1, Xb, Xb1, Xc, Xc1, Xd, Xd1, R1, R1a, R2, R2a, R3, R4, R4a, R5, R6, R6a, R7, R7a, R8, and R8a are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.