Abstract
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.
Original language | English |
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Pages (from-to) | 2982-2990 |
Number of pages | 9 |
Journal | ChemBioChem |
Volume | 21 |
Issue number | 20 |
DOIs | |
Publication status | Published - 15 Oct 2020 |
Keywords
- bacterial pathogens
- glycosides
- inflammation
- inhibitors
- lipopolysaccharides