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

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. NO response: We report on a remarkably efficient synthesis of the core lipoteichoic acid (LTA) anchor of the Streptococcus sp. DSM 8747, and derivatives thereof. Our syntheses are short (7–9 steps), convergent, and high yielding (33–37 %). The biological activity of these compounds is also investigated, with several analogues (particularly the sn‐1,2‐diacylglycerol LTA anchors) inducing macrophage activation.