β-Strand Mimetic Foldamers Rigidified through Dipolar Repulsion

Many therapeutically relevant protein-protein interactions contain hot-spot regions on secondary structural elements, which contribute disproportionately to binding enthalpy. Mimicry of such -helical regions has met with considerable success, however the analogous approach for the -strand has received less attention. Presented herein is a foldamer for strand mimicry in which dipolar repulsion is a central determinant of conformation. Computation as well as solution- and solid-phase data are consistent with an ensemble weighted almost exclusively in favor of the desired conformation.