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

Abstract

d-Glycero-d-manno-heptose-1β,7-bisphosphate (HBP) and dglycero-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 TIFAdependent NF-kB pathway. To better understand structurebased 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-kB 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-kB signaling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant.

TIFA promotes colorectal cancer cell proliferation in an RSK‐ and PRAS40‐dependent manner

“…Acting as an inflammation‐related adaptor protein, TIFA plays a vital role in various biological processes that include signal transduction in innate immunity, 9 , 38 , 39 , 40 , 41 inflammation, 42 , 43 hypoxia reoxygenation, 44 and cancer. Previous studies proved that TIFA plays different roles in various cancer types.…”

“…Taken together, the above results indicated that TIFA-mediated RSK signaling and PRAS40/mTOR signaling were mutually independent in an AKT/IKK-independent manner. Based on our findings, we propose the following model (Figure 7I Acting as an inflammation-related adaptor protein, TIFA plays a vital role in various biological processes that include signal transduction in innate immunity, 9,[38][39][40][41] inflammation, 42,43 hypoxia reoxygenation, 44 and cancer. Previous studies proved that TIFA plays different roles in various cancer types.…”

Stereoselective synthesis of d-glycero-d-manno-heptose-1β,7-bisphosphate (HBP) from d-mannurono-2,6-lactone

“…Noteworthy contributions include Sauvageau et al's synthesis of probes and derivatives to elucidate the inflammatory pathway induced by HBP, 6,7 and Vincent et al's synthesis of biotinylated analogs for identifying pathogen recognition receptor (PRRs) of bacterial metabolites, 8 and hydrolysis-resistant HBPs by substituting the anomeric oxygen with fluoromethylene. 9 We were also captivated by its intriguing bioactivity, prompting us to embark on the synthesis of the D-glycero-Dmanno-heptose skeleton and HBP through an innovative strategy.…”

Chemical Synthesis of a Keto Sugar Nucleotide

“…We assumed that, under this condition, the products could be epimerized at the α-positions of C-4-ketone, affording a mixture of diastereomers. As another option, the Mitsunobu phosphorylation of 7 was conducted . Despite several attempts, we were unable to obtain the desired 13 except that multicomponent mixtures were detected.…”