An unnatural amino acid that mimics a tripeptide beta-strand and forms beta-sheetlike hydrogen-bonded dimers

Unnatural amino acid 2 (5-HO2CCONH-2-MeO-C6H3-CONHNH2) duplicates the hydro gen-bonding functionality of one edge of a tripeptide P-strand. It is compo sed of hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid groups and is designated by the three-letter abbreviation "Hao" to reflect these thre e components. The 2,7-di-tert-butylfluorenylmethyloxycarbonyl (Fmoc*)- and tert-butyloxycarbonyl (Boc)-protected derivatives of Hao are prepared effic iently and in high yield by the condensation of suitably protected derivati ves of hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid. Fmoc*-Hao and Boc-Hao behave like typical Fmoc- and Boc-protected amino acids and ca n be incorporated into peptides by standard solid-and solution-phase peptid e synthesis techniques using carbodiimide coupling agents. Hao-containing p eptide 9 (i-PrCO-Phe-Hao-Val-NHBu) forms a beta-sheetlike hydrogen-bonded d imer in CDCl3 acid CD3OD-CDCl3 solutions. Peptides containing Hao and natur al amino acids display hydrogen-bonding surfaces that are complementary to the hydrogen-bonding edges of protein beta-sheets.