Studies on β-sheet forming oligourea foldamer

Abstract

The unnatural oligomers that adopt discrete conformations (“foldamers”) have recruited enormous attention because they can serve as excellent model systems to elucidate the fundamental questions in protein folding as well as their therapeutic potential in development of protein-protein interaction inhibitors. We have been especially interested in developing an autonomously folding β-sheet foldamer because it can be an inhibitor of aggregation process by β-sheet formation between the strands of α-peptide segments, which is known to cause Alzheimer diseases. Instead of using peptide-based foldamer, we designed an oligomer of urea that can autonomously folding β-sheet conformation since urea has been widely used as a denaturant of proteins due to its strong hydrogen bonding ability. A helix forming oligourea foldamer has been recently reported, but β-sheet forming oligourea remains unexplored. To achieve autonomous β-sheet formation of oligourea foldamer, the identification of an appropriate β-turn motif to connect two oligourea strands in juxtaposition is a critical step. Since the prolyl-(1,1-dimethyl)-1,2-diaminoethyl (Pro-DADME) unit has been known as a promoter of parallel sheet formation of α- or β-peptides, we synthesized a series of β-turn units composed of D-Pro with several diamines as well as L-Pro with diamines. It is well documented that the stabilization of particular conformational features by the introduction of particular constraints may be of major interest for the establishment of structure-activity relationship. After examination of the relative stability of the turn units in solution, we could identify a new turn motif derived from D-Pro and cis-1,2-cyclohexyldiamine in solution using various methods such temperature coefficient, NMR, solvent titration etc. We also obtained a single crystal of the desired β-turn which could be a direct proof of the type of natural β-turn, where 10 and 12-member ring exist. Recently, a class of synthetic p...