Research Highlights

Glycopharmacology: Mannoside mania

DM54 and DM58, two of the synthesized mannoside structures. © 2007 Oxford University Press.

Expression of MT1-MMP has numerous consequences for cell development and mediates, as a prerequisite for cell migration, cytoarchitecture reorganization. Cell surface glycan crosslinking by concanavalin A lectin (ConA) is known to induce MT1-MMP expression; thus, ConA treatment mimics the binding of glycans by neighboring cells and subsequently promotes MT1-MMP expression in vivo. Synthetic glycans, in contrast, block these glycan-related cell communication processes and may have therapeutic value in attenuating tumor-related cell migration facilitated by MT1-MMP expression. For example, vessel-forming progenitor cells derived from MSCs have been shown to be recruited by tumors in a process that likely involves MT1-MMP upregulation. In Glycobiology, Fortier et al. now present a new series of synthetic multivalent mannosides that block the effects of MSC glycan binding mimicked by ConA.

In screening a panel of chemically synthesized dendritic mannosides (glycodendrimers), the authors found that those that contained four or six mannose residues connected by phenyl rings (phenyl mannosides; see figure) were most effective in inhibiting the actions of ConA in cultured MSCs. When Fortier et al. incubated MSCs together with the phenyl mannosides, they found that the synthetic sugars prevented MSC aggregation and cytoskeletal rearrangement, in part, by blocking proMMP-2 activation. ProMMP-2 activation also correlated with caspase-3 induction and apoptosis, indicating that the polyvalent phenyl mannosides counteract ConA-induced pro-apoptotic signaling in MSCs. Interestingly, the tetravalent DM58 mannoside, which differs from DM54 in the linkage and the resulting orientation of the mannose molecules (see figure), had the strongest pro-survival effects as it exclusively reduced the number of apoptotic cells in the sub-G1 phase of the cell cycle. Similarly, DM58 was the most effective mannoside in preventing MSC aggregation and cytoskeleton disruption. However, each of the phenyl mannosides was able to inhibit ConA-induced proteolytic processing of MT1-MMP on the MSC surface, which precedes proMMP-2 activation.

These results show how the consequences of glycan recognition in MSCs can be eliminated to various degrees by synthetic sugar structures, as revealed by the differences between the effects of DM54 and DM58 in promoting MSC apoptosis. In addition, this study serves as an important reminder that small stereochemical differences of synthetic sugars can have profound consequences for their pharmacological application.

Author: Mirko von Elstermann