Cyclic Dinucleotide STING Modulator via Carbocyclic Nucleotide

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Solution Overview

Problem

Current therapies for viral infections, cancers, and inflammatory diseases lack effective stimulators of the innate immune system, particularly in modulating the STING adaptor protein to induce type I interferons and cytokines, which are crucial for immune response activation.

Innovation Solution

Development of novel 3′3′-cyclic dinucleotides that bind to and activate the STING adaptor protein, enhancing the production of type I interferons and cytokines, thereby modulating the immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If conventional therapies are used for viral infections, cancers, and inflammatory diseases, then treatment options are limited, but the innate immune system cannot be effectively stimulated to produce robust immune responses

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidimmune response activation

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies the chemical structure of cyclic dinucleotides by incorporating carbocyclic nucleotide analogues with specific substitutions (e.g., 2'-deoxy-2'-fluoro-cGAMP, 2'-deoxy-2'-methoxy-cGAMP) to enhance binding affinity to STING and improve immunostimulatory activity, thereby achieving more reliable and effective immune response activation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures by combining carbocyclic nucleotide analogues with cyclic dinucleotide frameworks, producing hybrid molecules that exhibit enhanced stability and potentiation of STING signaling, resulting in superior therapeutic effectiveness compared to conventional single-component therapies

Inventive Principle:

Principle #40Composite materials

2Reliability

If STING adaptor protein is activated to induce type I interferons and cytokines, then immune response is enhanced, but the mechanism for achieving this activation is insufficient in current therapies

Engineering Contradiction:

Improveimmune response activationVSAvoidtherapy development

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs small molecule cyclic dinucleotide analogues as transient, easily synthesizable compounds that can be rapidly produced and administered, providing a practical solution for developing accessible therapies that effectively activate STING without requiring complex or expensive manufacturing processes

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The carbocyclic nucleotide analogues serve as intermediary molecules that bridge the gap between external therapy and STING activation, efficiently mediating the signal transduction cascade that leads to type I interferon and cytokine production, thereby simplifying the overall therapeutic mechanism

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11766447B23′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator

Publication Date: 2023.09.26 INST OF ORGANIC CHEM & BIOCHEMISTRY OF THE ACAD OF SCI OF THE CZECH REPUBLIC

AI summary

The present disclosure relates to 3′3′-cyclic dinucleotides having a carbocyclic nucleotide and derivatives that can modulate the activity of the STING adaptor protein.