C4'-Me-modified 2',3'-cGAMP elicits a robust innate immune response in cells harboring the loss-of-function...

Area of Science:

• Immunology
• Biochemistry
• Medicinal Chemistry

Background:

• 2',3'-cyclic GMP-AMP dinucleotide (2',3'-cGAMP) activates STING, crucial for innate immunity and potential therapies.
• Clinical use of 2',3'-cGAMP is limited by poor stability, cell penetration, and efficacy in STING variants like R232H.

Purpose of the Study:

• To design and synthesize a modified 2',3'-cGAMP analogue with improved therapeutic properties.
• To evaluate the structural and functional characteristics of the novel analogue, particularly in STING-R232H expressing cells.

Main Methods:

• Chemical synthesis of a C4'-methyl-guanosine modified analogue (2',3'-cG4'-MeAMP).
• Structural analysis using NMR spectroscopy and molecular dynamics simulations.
• Assessment of nuclease resistance, serum stability, and innate immune response in human cells.

Main Results:

• The C4'-Me modification caused minimal structural changes.
• 2',3'-cG4'-MeAMP demonstrated enhanced resistance to 3' exonucleases and improved serum stability.
• The analogue elicited a superior innate immune response in STING-R232H variant cells compared to native 2',3'-cGAMP.

Conclusions:

• 2',3'-cG4'-MeAMP is a promising STING agonist with improved stability and efficacy.
• This analogue represents a potential therapeutic strategy for infections, cancer, and autoimmune diseases, especially in patients with the STING-R232H variant.