The stimulator-of-
interferon-gene (
STING)
protein is involved in innate immunity. The
drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-
STING (mSTING) agonist but had little effect on human-
STING (hSTING). In this paper, we draw upon the comparison of different crystal structures and
protein-
ligand interaction relationships analysis to venture the hypothesis that the
drug design of
DMXAA variants has the potential to convert
STING agonists to inhibitors. Based on our previous discovery of two
DMXAA analogs, 3 and 4 (both could bind to
STING), we structurally optimized them and synthesized new derivatives, respectively. In binding assays, we found compounds 11 and 27 to represent
STING binders that were superior to the original structures and discussed the structure-activity relationships. All target compounds were inactive in cellular assays for the screening of
STING agonistic activity. Gratifyingly, we identified 11 and 27 as
STING inhibitors with micromolar activity in both hSTING and mSTING pathways. In addition, 11 and 27 inhibited the induction of
interferon and inflammatory
cytokines activated by 2'3'-cGAMP without apparent cytotoxicity. These findings break the rigid thinking that
DMXAA provides the structural basis specifically for
STING agonists and open up more possibilities for developing novel
STING agonists or inhibitors.