3′3′-Cyclic Phosphonate Dinucleotides for STING Activation
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Solution Overview
Problem
Current cyclic dinucleotides used to activate the STING adaptor protein are susceptible to hydrolysis by phosphodiesterases in tissues and bodily fluids, limiting their effectiveness as anti-viral, anti-cancer agents, and vaccine adjuvants.
Innovation Solution
Development of novel 3′3′-cyclic phosphonate dinucleotides with a phosphonoalkyl bond instead of a phosphoester bond, which is resistant to hydrolysis, to bind and activate the STING protein, stimulating interferon and cytokine production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cyclic dinucleotides with phosphoester bonds are used to activate STING protein, then immune response stimulation is achieved, but the compounds are susceptible to hydrolysis by phosphodiesterases, limiting their effectiveness and duration of action
Solution Approach 1:
The patent applies parameter changes by modifying the chemical bond type from phosphoester to phosphonate, which fundamentally alters the hydrolytic stability parameter. This substitution replaces the hydrolytically labile phosphoester bond with a more stable phosphonate bond, thereby resolving the contradiction between maintaining biological activity and improving chemical stability in physiological conditions.
Solution Approach 2:
The invention creates composite molecular structures by combining the phosphonate linkage with cyclic dinucleotide motifs (including 2′3′-cGAMP, 3′3′-cGAMP, 2′2′-cGAMP, and their 5′-monophosphates). This composite approach integrates the stability-conferring phosphonate group with the STING-active cyclic dinucleotide core, achieving both hydrolytic resistance and immunostimulatory function.
2Productivity
If cyclic dinucleotides are used as vaccine adjuvants to enhance immune response, then immune activation is improved, but rapid degradation by phosphodiesterases reduces their duration of action
Solution Approach 1:
The patent modifies the chemical parameter of bond stability by substituting phosphoester with phosphonate linkages, thereby extending the duration of action of cyclic dinucleotide adjuvants. This parameter change prevents rapid enzymatic degradation, allowing the adjuvant to maintain immune-stimulating activity for prolonged periods.
Solution Approach 2:
The invention achieves sufficient immune activation through the stable phosphonate-containing cyclic dinucleotides without requiring continuous replenishment or high doses, as the extended half-life provides sustained exposure to the immune system, effectively resolving the duration limitation.
3Reliability
If phosphoester bonds are used in cyclic dinucleotides for STING activation, then biological activity is achieved, but susceptibility to enzymatic hydrolysis reduces reliability
Solution Approach 1:
The patent converts the harmful susceptibility to phosphodiesterase-mediated hydrolysis into a beneficial feature by using the enzyme's preference for phosphoester bonds as a design guide. By deliberately selecting phosphonate bonds that are resistant to these enzymes, the invention creates compounds that evade enzymatic degradation, thereby improving reliability and persistence of action.
Solution Approach 2:
The fundamental parameter change from phosphoester to phosphonate bonding alters the chemical recognition profile, making the cyclic dinucleotides invisible to phosphodiesterases while maintaining STING protein recognition and activation capability.
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 dinucleotides effectively activate the STING protein, inducing interferon and cytokine production, offering potential as anti-viral agents, anti-cancer therapies, and vaccine adjuvants with enhanced stability and efficacy.
Implementation Method 1
The cyclic dinucleotides of the invention are believed to be useful in treating diseases in which modulation of STING adaptor protein is beneficial... An advantage compared to the previously disclosed CDNs is believed to arise from the replacement of a phosphoester bond with a phosphonoalkyl bond that is resistant toward hydrolysis by phosphodiesterases present in tissues and bodily fluids.
Implementation Method 2
novel 3′3′-cyclic phosphonate dinucleotides with a phosphonoalkyl bond instead of a phosphoester bond, which is resistant to hydrolysis, to bind and activate the STING protein, stimulating interferon and cytokine production.
Data Source
AI summary
The present invention relates to 3′3′-cyclic dinucleotides modified with a 3′-phosphonoalkyl bond and derivatives thereof, that can modulate the activity of the STING adaptor protein.