Conformationally Restricted beta-Sheet Breaker Peptides Incorporating Cyclic alpha-Methylisoserine Sulfamidates

Peptides containing variations of the beta-amyloid hydrophobic core and five-membered sulfamidates derived from beta-amino acid alpha-methylisoserine have been synthesized and fully characterized in the gas phase, solid state and in aqueous solution by a combination of experimental and computational techniques. The cyclic sulfamidate group effectively locks the secondary structure at the N-terminus of such hybrid peptides imposing a conformational restriction and stabilizing non-extended structures. This conformational bias, which is maintained in the gas phase, solid state and aqueous solution, is shown to be resistant to structure templating through assays of in vitro beta-amyloid aggregation, acting as beta-sheet breaker peptides with moderate activity.