SYNTHESIS OF A PROTECTED PEPTIDE CORRESPONDING TO RESIDUES-1-25 OF THE BETA-AMYLOID PROTEIN OF ALZHEIMERS-DISEASE

The deposition of proteinaceous amyloid plaque in the brain is a characteristic of Alzheimer's disease. These plaques are composed of the 42 amino acid beta-amyloid protein (beta-A4), the sequence of which has been determined. beta-A4 is deposited in the brain as a noncrystalline, fibrous aggregate containing regular structure. Detailed structural studies of the beta-A4 aggregate require pure beta-A4 and various labeled analogs and sequence analogs. A convergent synthetic route to the beta-A4 protein has been designed to meet this need. This paper reports the synthesis, by solid-phase fragment coupling, of a 25-residue protected peptide corresponding to residues 1-25 of beta-A4. This peptide was prepared from four protected fragments which were coupled sequentially on the Kaiser oxime resin. Deprotection of the intermediate fragments led to the discovery of aspartimide formation at one site. The protection strategy and the deprotection conditions were adjusted to eliminate the undesired rearrangement.