3′3′ Cyclic Phosphonate Dinucleotides for Hydrolysis Resistance
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Solution Overview
Problem
There is a need for novel cyclic dinucleotides that activate the STING protein to stimulate interferon and cytokine production, as existing compounds are susceptible to hydrolysis by phosphodiesterases in tissues and bodily fluids, limiting their efficacy in treating diseases such as inflammation, autoimmune disorders, cancer, and viral infections.
Innovation Solution
Development of 3′3′ cyclic phosphonate di-nucleotides that replace phosphoester bonds with phosphonate bonds, providing resistance to hydrolysis by phosphodiesterases and effectively binding to and activating the STING protein, thereby inducing interferon and cytokine production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phosphoester bonds are used in cyclic dinucleotides, then the compounds can be synthesized and structurally simple, but they are susceptible to hydrolysis by phosphodiesterases in tissues and bodily fluids, limiting their efficacy
Solution Approach 1:
The patent applies parameter changes by substituting the phosphoester bond (P=O with -O-) with a phosphonate bond (P=O with -CH2- or other non-oxygen linkers). This chemical parameter change fundamentally alters the bond's resistance to hydrolysis, making it resistant to phosphodiesterase enzymes while maintaining the cyclic dinucleotide's ability to activate STING and produce interferons.
2Stability of the object's composition
If phosphonate bonds replace phosphoester bonds, then hydrolytic stability is improved, but the structural complexity and synthesis difficulty increase
Solution Approach 1:
The patent systematically explores various phosphonate bond configurations (different linkers between phosphorus and carbon, such as -CH2-, -C(R)2-, etc.) to find optimal balances between stability and synthesizability. By varying these chemical parameters, the patent develops a series of compounds with different degrees of synthetic complexity while maintaining the desired hydrolytic stability.
3Duration of action of moving object
If existing cyclic dinucleotides are used, then they can activate STING protein, but their duration of action is limited due to rapid hydrolysis in biological systems
Solution Approach 1:
The patent addresses duration of action by changing the chemical stability parameter through phosphonate substitution. The resulting compounds resist enzymatic degradation, allowing them to persist longer in biological systems and maintain STING activation over extended periods, thereby improving both duration and reliability of therapeutic effect.
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
The novel 3′3′ cyclic phosphonate di-nucleotides effectively activate the STING protein, offering potential as anti-viral and anti-cancer agents, vaccine adjuvants, and treatments for inflammatory and autoimmune diseases by enhancing interferon and cytokine production.
Implementation Method 1
replacement of a phosphoester bond with a phosphonate bond that is resistant toward hydrolysis by phosphodiesterases present in tissues and bodily fluids
Implementation Method 2
bind to and activate protein STING and, consequently, stimulate the signal transduction pathway that induces interferons and other cytokines/chemokines
Data Source
AI summary
The present disclosure describes 3′3′ cyclic phosphonate dinucleotides of general formula (J), their pharmaceutically acceptable salts, their pharmaceutical composition and combinations of substances and other medicaments or pharmaceuticals. The disclosure also describes the use of compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. These substances can be used as adjuvants in vaccines.