Insights into Selectin Inhibitor Design from Endogenous Isomeric Ligands of SLe(a) and SLe(x)

Selectins interact with cell-surface glycans to promote the initial tethering and rolling of leukocytes, and these interactions are targets for designs of inhibitors to neutralize diseases related to excessive inflammatory responses in many cardiovascular and immune dysfunctions, as well as tumor markers in different cancers. The isomeric endogenous tetrasaccharides, sialyl Lewis X (sLe(x)) and sialyl Lewis A (sLe(a)), are minimal sugar structures required for selectin binding. Understanding their subtle structural variances and significant advanced binding strengths of sLe(a) over sLe(x) could benefit the rational designs for selectin inhibitors. Modeling based on the E-selectin-sLe(x) crystal structure in the present study demonstrated that the N-acetyl group of GlcNAc in sLe(x) could form steric hindrances in the E-selectin-sLe(x) complex, but the hydroxy methylene group of GlcNAc in sLe(a) at the same position allows for stronger binding interactions. The subsequent designed inhibitor with a synthetic accessible linker molecule that has no exo-cyclic moieties replacing GlcNAc displayed comparable dynamic and energetic binding features to sLe(a). The present study deciphered the clues from endogenous isomeric sLe(a) and sLe(x) and provided insights into designing selectin inhibitors with simplified synthesis.