The important contribution of cell surface carbohydrates to microbial adhesion onto mucosal surfaces has motivated the design of synthetic glycoconjugates as potential antimicrobial agents. An immediate approach to mimick natural antibacterial strategies is to use the oligosaccharides that are found at concentrations as high as millimolar in human milk. Indeed, milk oligosaccharides are responsible for the protective effects of non-immunoglobulin fractions of human milk. However, the hydrophobic part of GSL receptors and, at least in some cases, cholesterol, have a profound impact on the orientation of the oligosaccharide moiety, so that free oligosaccharides have often a reduced affinity for ligand compared to the whole membrane-anchored GSL. Moreover, GSLreceptors are concentrated in lipid rafts, so that the free oligosaccharide may not been able to reach the local concentration and/or the active conformation of the carbohydrate binding domain of intact GSL receptors. For these reasons, two main strategies have been developed to increase the antimicrobial activity of carbohydrate-based candidate drugs. The first approach is to polymerize the oligosaccharide on a chemical matrix to obtain a multivalent neoglyconjugate. The other approach is to modify the structure of the hydrophobic part of GSL receptors with the aim to obtain water-soluble analogs in which the conformation of the binding domain of the analog is as close as possible to that of the GSL. Correspondingly, these analogs can be referred to as ‘glycolipidomimetics’ (16). Several synthetic analogs of GalCer have been synthesized, with interesting anti-HIV activity in vitro (20-22). The chemical structure of authentic GalCer (1) and synthetic analogs (2, 3) (23, 24) are shown below.