University of Namur (UNamur), NARILIS, Department of Chemistry, rue de Bruxelles 61, 5000, Namur, Belgium.
Academia Sinica, Institute of Biological Chemistry, 128, Academia Road Section 2, Nankang, 11529, Taipei, Taiwan.
Chembiochem. 2020 Oct 15;21(20):2982-2990. doi: 10.1002/cbic.202000319. Epub 2020 Jul 2.
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.
d-甘油基-d-甘露庚糖-1β，7-双磷酸（HBP）和 d-甘油基-d-甘露庚糖-1β-磷酸（H1P）是细菌代谢物，最近的研究表明，它们通过激活 TIFA 依赖性 NF-κB 途径，刺激宿主细胞的炎症反应。为了更好地理解与这一过程相关的基于结构的活性，合成了一系列非水解膦酸酯类似物的 HBP 和 H1P。在体内以低纳摩尔浓度（6 nM）评估了这些分子诱导 TIFA-NF-κB 信号轴的炎症调节作用，并与天然代谢物进行了比较。我们的数据表明，三种膦酸酯类似物具有与 HBP 相似的刺激活性，而两种膦酸盐则拮抗 HBP 诱导的 TIFA-NF-κB 信号。这些结果为设计促炎和先天免疫调节剂开辟了新的前景，这些调节剂可用作疫苗佐剂。
