Synthesis and Biological Activity of the Lipoteichoic Acid Anchor from Streptococcus sp. DSM 8747

Abstract

In this study, the role of lipoteichoic acid (LTA) anchors in the activation of the innate immune response was investigated through the chemical synthesis of a series of LTA derivatives and the determination of their ability to induce NO production in bone marrow-derived macrophages (BMM). To this end, an efficient synthesis of the sn-3-O-(α-D-galactofuranosyl)-1,2-di-O-acylglycerol LTA core was developed, which was then used as a key structure to produce both phosphate and glycerylphosphate-funtionalised LTA anchors, as well as galactofuranosyldiglycerides with different fatty acid chain lengths. With a series of LTA anchors in hand, we then determined the effect of these glycolipids on the innate immune response by exploring their capacity to activate macrophages. Here, we report that several of the LTA-derivatives were able to induce NO production by BMMs. In general, the unnatural (sn-1) core glycolipid anchors showed lower levels of activity than the corresponding natural (sn-3) analogues, and the activity of the glycolipids also appears to be dependent on the length of lipid present, with an optimum lipid length of C20 for the sn-3 derivatives. Interestingly, a triacylated anchor and the 6-O-phosphorylated anchor, showed only modest activity, while the 6-O-glycerophosphorylated derivative was unable to induce NO production. Taken as a whole, our results highlight the subtle effects that glycolipid length can have on the ability to activate BMMs.

Total Synthesis of Five Lipoteichoic acids of Clostridium difficile

“…Recently the biological active type 1 LTA from Streptococcus species DSM 8747 has been synthesized by Qiao et al 14. and Sauvageau et al 15. Total synthesis of a derivative of the more complex LTA from S. pneumoniae has also been achieved16 and its interaction with the host immune system revealed that not TLR‐2 but the complement pathway was activated 17.…”

“…[12] Several unnatural derivatives were synthesized and probed in innate immunological studies to clarify the biological pathway. [13] Recently the biological active type 1 LTA from Streptococcus species DSM 8747 has been synthesized by Qiao et al [14] and Sauvageau et al [15] Total synthesis of a derivative of the more complex LTA from S. pneumoniae has also been achieved [16] and its interaction with the host immune system revealed that not TLR-2 but the complement pathway was activated. [17] Since the structural motive is very different between the families of LTAs, and dependent on the origin, a different biological pathway is not a surprise, but what about other LTAs from other Gram-positive bacteria?…”

Expedient synthesis of 1,6-anhydro-α-D-galactofuranose, a useful intermediate for glycobiological tools

“…Thus, while compounds 13 [38] and 14 [39] were prepared by treatment with Lewis acids of fully protected precursors and proved to be stable and therefore useful as synthetic intermediates, attempts to prepare compound 15 by treatment with BF 3 ·OEt 2 of the persilylated precursor failed and inevitably led to the anhydro derivative 12 . Moreover, whereas treatment with TFA/THF/H 2 O 90:5:2.5 of 4-nitrophenyl per- O -TBS-α-D-Ara f afforded 16 , 4-nitrophenyl per- O -TBS-β-D-galactofuranoside did not lead to compound 15 under the same conditions and compound 12 was obtained instead (Fig.…”

Synthetic tools for the characterization of galactofuranosyl transferases: glycosylations via acylated glycosyl iodides

“…DSM 8747 has been synthesized by glycosylation of 9 via the galactofuranosyl iodide, and the method showed to be significantly more efficient than those using traditional glycosyl donors. 28 Condensation of persilylated 9…”