Cell surface glycans, depending on their structures and dynamic modifications, act as the first point of contact and regulate cell-cell, cell-matrix, and cell-pathogen interactions. Particularly, the sialyl-Lewis-X (sLeX, CD15s) tetrasaccharide epitope, expressed on both glycoproteins and gangliosides, participates in leukocyte extravasation via interactions with selectins expressed on endothelial cells, lymphocytes, and platelets (CD62-E/L/P). Neutrophils carrying sLeX epitopes are thought to be responsible for chronic inflammatory diseases resulting in plaque formation and atherosclerosis. Intense efforts have been devoted to the development of sLeX mimetics for inhibition of cell adhesion. On the other hand, dysregulated expression of sLeX and poor extravasation are the major underlying causes of leukocyte adhesion deficiency-II (LAD-II) disorders that result in frequent infections and poor immune response. We hypothesized that metabolic processing of peracetyl N-(cycloalkyl)acyl-D-mannosamine derivatives, through the sialic acid pathway, might result in the expression of sialoglycans with altered hydrophobicity which in-turn could modulate their binding to endogenous lectins, including selectins. Herein, we show that treatment of HL-60 (human acute myeloid leukemia) cells with peracetyl N-cyclobutanoyl-D-mannosamine (Ac4ManNCb), at 50 microM for 48 h, resulted in a robust three to four fold increase in the binding of anti-sLeX (CSLEX1) antibody and enhanced cell adhesion to E-selectin coated surfaces; while the corresponding straight-chain analogue, peracetyl N-pentanoyl-D-mannosamine (Ac4ManNPent), and peracetyl N-cyclopropanoyl-D-mannosamine (Ac4ManNCp) both resulted in 2.0-2.5fold increase compared to controls. The ability to enhance sLeX expression using small molecules has the potential to provide novel opportunities to address challenges in the treatment of immune deficiency disorders.
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