Synthesis and Immunomodulatory Activities of Glycolipids Containing Characteristic Lipid Moieties

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Mini symposium: Glycobiology at the LUMC and beyond

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Synthesis and Immunomodulatory Activities of Glycolipids Containing Characteristic Lipid Moieties

Yohei Arai 1 , Toshihiko Aiba 1,2 , Ryota Saito 1 , Natsumi Hirata 1 , Takanori Matsumaru 1 , Shinsuke Inuki 1,3 , Yukari Fujimoto 1

1 Faculty of Science and Technology, Keio University, Yokohama-shi, Japan, 2 Graduate School of Science, Osaka University, Toyonaka-shi, Japan, 3Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Japan

Various microbial cell membrane glyco-/lipid-conjugates are recognized by innate immune receptors such as TLRs, CLRs, and lipid antigen-presenting molecules, CD1, which lead to release of various cytokines and activate the immune system. For the recognition of the glyco/lipid-conjugates, the lipid moieties bind to hydrophobic binding pocket of the receptors, such as TLR2, TLR4 and CD1d. We focused on a few polar residues in the hydrophobic pocket of the lipid recognition receptors, expecting their stronger shielded hydrogen-bond in the hydrophobic pocket [1, 2]. We designed the ligands containing polar functional groups in the lipid chain, which was expected to interact with the hydrophilic regions of the binding pocket, in order to improve the immunomodulatory activities and selective activation of the lipid recognition receptors. Namely, several glyco-/lipid-conjugates such as α-GalCer, Pam2CSK4, and phosphatidylinositols, which contain polar functional groups in the lipid chain, were synthesized (Figure 1). The results of the binding assay, cytokine induction assay and MD simulation (with TLR2 or CD1d) using the ligands showed that the position of polar group in the acyl chain influenced the ligand activities, presumably because the polar functional group interacted with the hydrophilic regions of the binding pocket in TLR2 and CD1d. Moreover, the designed -GalCer displayed higher binding affinities and cytokine production activities compared to the CD1d ligand containing an unmodified lipid chain. These results suggested that the polar functional groups may specifically interact with polar residues in the lipid binding pocket, and these residues may be a target for the regulation of ligand recognition and the biological activities[3,4,5].

Structures of glyco-/lipid-conjugates containing characteristic lipid moieties

Gao, J.; Bosco, D. A.; Powers, E. T.; Kelly, J. W. Nat. Publ. Gr. 2009, 16, 684-90.

Schmidtke, P.; Luque, F. J.; Murray, J. B.; Barril, X. J. Am. Chem. Soc. 2011, 133, 18903-10.

Inuki, S.; Aiba, T.; Hirata, N.; Ichihara, O.; Yoshidome, D.; Kita, S.; Maenaka, K.; Fukase, K.; Fujimoto, Y. ACS Chem. Biol. 2016, 11, 3132-9.

Inuki, S.; Kashiwabara, E.; Hirata, N.; Kishi, J.; Nabika, E.; Fujimoto, Y. Angew. Chem. Int. Ed. 2018, 57, 9655-9.

Arai, Y.; Inuki, S.; Fujimoto, Y. Bioorg. Med. Chem. Lett. 2018, 28, 1638-41.

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