An Unnatural Amino Acid that Induces β-Sheet Folding and Interaction in Peptides

This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into β-sheetlike structures that dimerize through β-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the β-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654−7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a β-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling age...