Development of nitroalkene-based inhibitors to target STING-dependent inflammation

Area of Science:

• Immunology
• Medicinal Chemistry

Background:

• Stimulator of Interferon Genes (STING) is crucial for inflammatory responses to cytosolic DNA.
• Aberrant STING activation is implicated in numerous inflammatory diseases, yet effective inhibitors are lacking.
• Endogenous nitrated fatty acids were previously identified as reversible STING inhibitors.

Purpose of the Study:

• To develop and evaluate novel nitroalkene-based compounds as specific and effective STING inhibitors.
• To improve upon existing nitrated fatty acid STING inhibitors.

Main Methods:

• Synthesized and tested a library of nitroalkene compounds for STING inhibition.
• Conducted structure-activity relationship studies, focusing on conjugation with aromatic moieties.
• Evaluated lead compounds (CP-36, CP-45) in vitro and in vivo models.

Main Results:

• Nitroalkene conjugation with aromatic moieties enhanced electrophilicity and reduced conformational flexibility.
• Lead compounds CP-36 and CP-45, containing a β-nitrostyrene core, demonstrated potent in vitro STING inhibition.
• These compounds effectively alleviated STING-dependent inflammation in vivo.

Conclusions:

• Nitroalkene compounds represent a promising class of drug candidates for STING modulation.
• The developed compounds offer robust leads for preclinical development in treating STING-driven inflammatory conditions.