Nonhydrolyzable Heptose Bis‐ and Monophosphate Analogues Modulate Pro‐inflammatory TIFA‐NF‐κB Signaling

d ‐ Glycero ‐ d ‐ manno ‐heptose‐1β,7‐bisphosphate (HBP) and d ‐ glycero ‐ d ‐ manno ‐heptose‐1β‐phosphate (H1P) are bacterial metabolites that were recently shown to stimulate inflammatory responses in host cells through the activation of the TIFA‐dependent NF‐κB pathway. To better understand structure‐based activity in relation to this process, a family of nonhydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA‐NF‐κB signal axis was evaluated in vivo at a low‐nanomolar concentration (6 nM) and compared to that of the natural metabolites. Our data showed that three phosphonate analogues had similar stimulatory activity to HBP, whereas two phosphonates antagonized HBP‐induced TIFA‐NF‐κB signaling. These results open new horizons for the design of pro‐inflammatory and innate immune modulators that could be used as vaccine adjuvant.