Alternate synthesis to d -glycero-β- d -manno-heptose 1,7-biphosphate

Sauvageau, Janelle; Bhasin, Milan; Guo, Cynthia X.; Adekoya, Itunuoluwa; Gray-Owen, Scott D.; Oscarson, Stefan; Guazzelli, Lorenzo; Cox, Andrew D.

doi:10.1016/j.carres.2017.08.011

Cited by 10 publications

(16 citation statements)

References 18 publications

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“…In line with IL-8 data, bHBP induced the formation of large TIFA-GFP oligomers in a dose-dependent manner ( Fig 2C and D). This result was in agreement with previous reports showing that synthetic bHBP induces NF-jB activation after several hours of treatment [15,16]. Given that TIFA oligomerization is observed within minutes of S. flexneri, S. typhimurium, or H. pylori infections [3,11], we also monitored TIFA oligomerization after 30 min of treatment.…”

Section: Resultssupporting

confidence: 92%

“…bHBP was also chemically synthesized [14][15][16][17]. Its pro-inflammatory activity was validated on the basis that it induced NF-jB activation after several hours of treatment [15,16]. In this report, we compare the ability of chemically synthesized bHBP and S. flexneri lysate to induce TIFA oligomerization and IL-8 production in human epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

et al. 2018

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During an infection, the detection of pathogens is mediated through the interactions between pathogen‐associated molecular patterns (PAMPs) and pathogen recognition receptors. β‐Heptose 1,7‐bisphosphate (βHBP), an intermediate of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a bacterial PAMP. It was reported that βHBP sensing leads to oligomerization of TIFA proteins, a mechanism controlling NF‐κB activation and pro‐inflammatory gene expression. Here, we compare the ability of chemically synthesized βHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. We find that, unlike bacterial lysate, βHBP fails to initiate rapid TIFA oligomerization. It only induces delayed signaling, suggesting that βHBP must be processed intracellularly to trigger inflammation. Gene deletion and complementation analysis of the LPS biosynthesis pathway revealed that ADP‐heptose is the bacterial metabolite responsible for rapid TIFA oligomerization. ADP‐heptose sensing occurs down to 10−10 M. During S. flexneri infection, it results in cytokine production, a process dependent on the kinase ALPK1. Altogether, our results rule out a major role of βHBP in S. flexneri infection and identify ADP‐heptose as a new bacterial PAMP.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

et al. 2018

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“…1), we synthesized the different analogs of b-HBP illustrated in Fig. 2 using methods described in previous reports (9,13,14) and then confirmed their purity and identity using NMR, MS spectrometry, and HPAEC (Tables I, II). Fig.…”

Section: Resultsmentioning

confidence: 97%

“…b-MP was synthesized from acetylated D-mannose using the methods described in Zamyatina et al (14). b-HBP and a-HBP were synthesized as described by Sauvageau et al (9). Compound purity and identity were measured using 1 H NMR, MS, and a high-performance anion exchange chromatography (HPAEC) system.…”

Section: Chemical Structuresmentioning

confidence: 99%

“…The prolonged innate response of cells exposed to b-HBP, presumably stemming from the intracellular accumulation of this agonist (2), implies that b-HBP may be used to modulate immune responses in a wide variety of therapeutic applications, such as to promote HIV exit from latency in CD4 + lymphocytes (2) and to act as an adjuvant for both conventional vaccination and cancer immunotherapy. However, these translational studies have been hampered by the cost and technical difficulty in generating sufficient amounts of b-HBP from the established enzymatic or chemical synthesis approaches (3,(9)(10)(11)(12). Although the synthesis of a-anomeric phosphates is straightforward (9-12), the chemical synthesis of b-anomeric heptose phosphates is particularly difficult and inefficient.…”

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confidence: 99%

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

Adekoya

Guo

Gray-Owen

et al. 2018

The Journal of Immunology

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d-Glycero-β-d-manno-heptose 1,7-biphosphate (β-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 β-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-β-d-manno-heptose 1-phosphate (β-HMP) induced TIFA-dependent NF-κB activation and cytokine production in a manner similar to β-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.

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

Liang

Wei

et al. 2020

ChemBioChem

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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.

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Alternate synthesis to d -glycero-β- d -manno-heptose 1,7-biphosphate

Cited by 10 publications

References 18 publications

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

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

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

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