Oxadiazole grafts in peptide macrocycles

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Dr. Yudin's group has developed a versatile approach to rapidly access structurally diverse macrocyclic peptides via a reaction between readily accessible components, namely, a linear peptide, aldehyde, and (N-isocyanimino) triphenylphosphorane (Pinc). A unique and enabling feature of this approach involves the formation of an unprecedented motif in the form of a contiguous non-amidated N-terminal amino group, variable aldehyde, and 1,3,4-oxadiazole triad inserted directly into the peptide backbone. This new linkage displays a remarkably well-conserved conformational geometry, independent of the peptidic or aldehyde components, and serves as an endocyclic control element that stabilizes turn motifs thereby promoting passive membrane permeability. This, in turn, facilitates oral bioavailability of oxadiazole-containing macrocycles. ß-Turns are present in a number of biologically active peptides, supporting the application of this methodology for the development of new therapeutics and biological probes.