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

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

Chembiochem. 2020 Oct 15; 21(20):2982-2990. Epub 2020 Jul 2.
doi: 10.1002/cbic.202000319

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摘要

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- k B pathway . To better understand the structure-based activity in relation to this process, a family of non-hydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA-NF- κ B signal axis was evaluated in vivo at a low-nanomolar concentration (6 nM) and compared to the natural metabolites. Our data showed that three phosphonate analogues resembled the stimulatory activity of HBP, while two phosphonates antagonized the HBP-induced TIFA-NF- κ B signalling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant.