Replacement of the peptide bond with a surrogate alkene substructure is one of the promising approaches to probe structural and electrostatic requirements in bioactive and functional peptides. Our group has focused on the synthetic and application studies of haloalkenes, which has thought to have favorable electrostatic and steric properties as peptide bond isostere. Chloroalkene dipeptide isosteres (CADIs) is expected to be one of the ideal peptide bond isosteres having the high peptide bond mimicry by chlorine-derived steric and electronic properties. As part of our projects aimed at developing peptidomimetic tools, we focused on the amyloid β (Aβ) fragment peptide 1 (Ac-KLVFFAE-NH2) which have been reported to form insoluble amyloid fibrils composed of antiparallel beta sheet structure. The intermolecular H-bonding interactions of peptide bonds between Phe4-Phe5 has reported to be critical for aggregation. These results guided us to the application study of CADI to the aggregation form analysis of Aβ fragment peptide that allows the precise investigation of the role of the peptide bond of Phe-Phe sequence in the fibrillization. In this presentation, we will demonstrate the preparation of peptidomimetic containing Phe-Phe-type (Z)-CADI by utilizing our synthetic approach, and application to the Aβ fragment peptide 1 for amyloid fibril formation. Thus, the contributions of the Phe4-Phe5 peptide bond to the amyloid fibril formation of peptide 1 were investigated through the AFM imaging and △△G of peptidomimetic 2 containing the Phe-Phe-type (Z)-CADI. Furthermore, the comparative study with the corresponding peptidomimetic containing Phe-Phe-type (E)-methylalkene dipeptide isosteres for the details of mechanisms of contribution of chlorine atom will be discussed.

Aggregation mechanism analysis of amyloid β fragment utilizing alkene-type peptide bond isosteres

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.