Siglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis and affinity measurements are complemented by high-quality models of sialoside-Siglec-7 complexes based on molecular dynamics (MD) simulations on the microsecond time scale. We provide details for the predicted binding modes for the new ligands, e.g., that an extension of the carbon backbone leads to a different molecular interaction pattern with the receptor and the nearby water structure than found for known Siglec-7 ligands. Further on, we uncover some shortcomings of the GLYCAM06 and GAFF2 force fields when used for the simulation of sialoside-based glycomimetics. Our results open new opportunities for the rational design of Siglec-7 inhibitors. In addition, we provide strategies on how to use and visualize MD simulations to describe and investigate sialoside-Siglec complexes in general.
Background/objectives: Tumor microenvironmental hypoxia is an established hallmark of solid tumors. It significantly contributes to tumor aggressiveness and therapy resistance and has been reported to affect the balance of activating/inhibitory surface receptors' expression and activity on NK cells. In the current study, we investigated the impact of hypoxia on the surface expression of Siglec-7 and Siglec-9 (Sig-7/9) and their ligands in NK cells and tumor target cells.
In the present work, bacterial glycosyltransferases are utilized to construct ganglioside glycans in a convergent approach via a sugar‒nucleotide regeneration system and one-pot multienzyme reactions. Starting from β-lactoside enables the diversification of both the glycan moieties and the linkages in the lower α-arm and upper β-arm. Overall, a comprehensive panel of 24 natural a-series (GM3, GM2, GM1a, GD1a, GT1a, and fucosyl-GM1), b-series (GD3, GD2, GD1b, GT1b, and GQ1b), c-series (GT3, GT2, GT1c, GQ1c, and GP1c), α-series (GM1α, GD1aα, and GT1aα), and o-series (GA2, GA1, GM1b, GalNAc-GM1b, and GD1c) ganglioside glycans are prepared, which are suitable for biological studies and further applications.
Siglec-7, an inhibitory receptor expressed on natural killer (NK) cells, recognizes sialic acid-containing glycans. However, the ligand glycan structures of Siglec-7 and its carrier proteins have not been comprehensively investigated. Here, we identified four sialyltransferases that are used for the synthesis of ligand glycans of Siglec-7 and two ligand O-glycan-carrier proteins, PODXL and MUC13, using a colon cancer line.
Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor-based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer.
Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells.
