D-Glycero-β-D-Manno-Heptose 1-Phosphate and D-Glycero-β-D-Manno-Heptose 1,7-Biphosphate Are Both Innate Immune Agonists

D-Glycero-beta-D-manno-heptose 1,7-biphosphate (beta-HBP) is a novel microbial-associated molecular pattern that triggers inflammation and thus has the potential to act as an immune modulator in many therapeutic contexts. To better understand the structure-activity relationship of this molecule, we chemically synthesized analogs of beta-HBP and tested their ability to induce canonical TIFA-dependent inflammation in human embryonic kidney cells (HEK 293T) and colonic epithelial cells (HCT 116). Of the analogs tested, only D-glycero-beta-D-manno-heptose 1-phosphate (beta-HMP) induced TIFA-dependent NF-kappa B activation and cytokine production in a manner similar to beta-HBP. This finding expands the spectrum of metabolites from the Gram-negative ADP-heptose biosynthesis pathway that can function as innate immune agonists and provides a more readily available agonist of the TIFA-dependent inflammatory pathway that can be easily produced by synthetic methods.