Achieving High Affinity and Selectivity for Asymmetric Dimethylarginine by Putting a Lid on a Box

The methylation states of Lys and Arg represent a particularly challenging set of targets to distinguish selectively in water using synthetic receptors. To date, Kme3 is the only post translational modification (PTM) of the eight possible methylation states of Lys and Arg that can be recognized selectively. Here we report the first synthetic receptor capable of selectively recognizing Rme2a. This was achieved using a biased DCC library to generate a receptor mimicking the 5‐sided box‐like shape of Rme2 reader proteins, a feature that has been hypothesized to impart selectivity. Additionally, we have synthesized a thioether‐linked analogue of the resulting receptor to provide a novel scaffold with maintained selectivity, but greater stability. This work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.

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