Cyclic β-sheet peptides

Our laboratory has developed a class of cyclic β-sheet peptides to study the folding and supramolecular assembly of β-sheets. The peptides consist of a peptide sequence of interest incorporated into a macrocycle with the β-strand mimic Hao and δ-linked ornithine units. The δ-linked-ornithine turn units help align the peptide sequence of interest with the Hao-containing template strand. The Hao β-strand mimic helps induce β-sheet folding and also blocks uncontrolled β-sheet interactions. The resulting macrocyclic peptides fold to adopt a β-sheet structure and may also undergo further supramolecular assembly to form tetramers or other oligomers through edge-to-edge and face-to-face interactions. This paper provides procedures for the synthesis of the Fmoc-protected Hao amino acid and additional procedures for the synthesis of macrocyclic β-sheet peptides containing the Hao amino acid and the δ-linked ornithine units. Fmoc-Hao is prepared on a multigram scale from hydrazine, 2-methoxybenzoic acid, and ethyl oxalyl chloride. The macrocyclic β-sheet peptides are synthesized in tens-of-milligram quantities through Fmoc-based solid-phase peptide synthesis followed by solution-phase macrocyclization, deprotection, and reverse-phase chromatographic purification.