Substituent-Dependent Turn Switching in RGGY Peptidomimetics Containing Alkene Dipeptide Isosteres

Alkene dipeptide isosteres are useful amide bond surrogates for controlling peptide conformation. To probe substituent effects in alkene dipeptide isosteres, we designed Arg-Gly-Gly-Tyr peptidomimetics in which the Gly-Gly peptide bond was replaced with either a methylalkene dipeptide isostere or a chloroalkene dipeptide isostere. Solution structures were analyzed using NOESY experiments and amide temperature-coefficient measurements. The methylalkene-type peptidomimetic exhibits NMR features consistent with a γ-turn-like conformation, whereas the chloroalkene-type peptidomimetic displays a distinct folded geometry approaching α-/ε-turn-like structures. These results indicate that subtle differences in the alkene substituent can induce switching of the preferred turn geometry within an identical peptide sequence. Such substituent-dependent effects highlight the potential of ADIs as backbone-editing elements for controlling peptide turn geometry.