STING activation by teniposide: a potential direct mechanism beyond cGAS stimulation

Area of Science:

• Immunology
• Drug Discovery
• Computational Biology

Background:

• The STimulator of Interferon Genes (STING) is a crucial protein in the innate immune system's response to cytosolic DNA.
• STING is a promising therapeutic target for immune modulation.

Purpose of the Study:

• To identify novel STING ligands using high-throughput virtual screening.
• To investigate the mechanism of action of Teniposide as a potential STING ligand.

Main Methods:

• High-throughput virtual screening to identify potential STING ligands.
• Isothermal titration calorimetry (ITC) to confirm direct binding.
• Computational docking and molecular dynamics simulations to characterize binding mode.

Main Results:

• Teniposide was identified as a potential STING ligand.
• Direct binding of Teniposide to STING was confirmed experimentally and computationally.
• Teniposide activated the IFN-β signaling pathway in a STING-dependent manner, independent of cGAS and IFI16.

Conclusions:

• Teniposide activates STING via a novel, cGAS-independent mechanism.
• Repurposing Teniposide as a STING agonist offers new therapeutic avenues for innate immune stimulation.