Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Cyclic dinucleotides (CDNs) are key signaling molecules that activate the innate immune system via the stimulator of interferon genes (STING) pathway.
• Understanding the structure-function relationship of CDNs is crucial for deciphering innate immune responses.
• The native archetype, cyclic di-guanosine monophosphate (c-di-GMP), is a potent inducer of type-I interferons (IFNs).

Purpose of the Study:

• To design and synthesize novel cyclic dinucleotide (CDN) analogues with modified nucleobases.
• To evaluate the immunostimulatory effects of these analogues on innate immune pathways.
• To establish a correlation between structural modifications and functional outcomes in CDN-mediated signaling.

Main Methods:

• Utilized an 'atomic mutagenesis' strategy, systematically altering one atom at a time in the CDN structure.
• Synthesized a series of gradually modified c-di-GMP analogues.
• Assessed the ability of synthesized analogues to induce type-I interferon (IFN) production in eukaryotic cells.

Main Results:

• Developed a novel class of c-di-GMP analogues with modified nucleobases.
• Demonstrated that these CDN analogues effectively induce type-I IFN production.
• Identified specific analogues that exhibit enhanced potency compared to the native c-di-GMP.

Conclusions:

• CDN analogues with modified nucleobases can effectively modulate the innate immune response.
• Structural modifications, achieved through atomic mutagenesis, allow for tuning of CDN immunostimulatory activity.
• These findings provide a foundation for developing novel immunomodulatory therapeutics targeting the STING pathway.