Biological processes like cell-pathogen interactions, immune response and inter-cell to cell communication, and disease progression are all mediated by cell-surface interactions. Glycoproteins, glycolipids, and glycopolymers together called the glycocalyx present on the cell's surface plays an important role in mediating these biological processes. Glycans present in the glycocalyx are unique identifiers of a cell type and also can indicate an abnormal or diseased cellular metabolism and thus could serve as potential drug targets. Small molecules like synthetic lectins are known to recognize cell surface glycans, however, they lack specificity and strong binding affinity. Synthetic carbohydrate receptors (SCRs) that bind to surface glycans could be used alternatively, but similar to synthetic lectins they too lack specificity. However, SCRs can be modified to achieve the required binding affinity and substrate selectivity. Previously we have reported a series of flexible SCRs based upon a biaryl core with four pendant heterocyclic groups that bind glycans selectively through noncovalent interactions. In this study, we varied the point of attachment of the pendant heterocyclic groups to the biaryl core and identified the relationships between tetrapodal SCR structure and trends in the binding data. We first show that the largest Log<i>β</i> values arise from non-stoichiometric binding, where the SCR can associate with more than one equivalent of a glycan. Second, small heterocycles (e.g. pyrrole, furan, thiophene, phenol) do not suffer from the size exclusion effect that sterically hinders the non-stoichiometric association and electron-rich heterocycles, draw the glycan away from the biaryl core. We also show that some SCRS are capable of forming intramolecular H-bonds, and doing so weakens the binding affinity<b> </b>because the glycan must overcome this intramolecular stabilization to form a host-guest complex. Together, these data provide a series of guidelines that anticipate how structural modifications affect the association between SCRs and carbohydrates for future tetrapodal SCRs design.

Tuning the binding affinity and selectivity of synthetic carbohydrate receptors

ACS Spring 2022

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