E-Olefin Dipeptide Isostere Incorporation into a Polypeptide Backbone Enables Hydrogen Bond Perturbation:  Probing the Requirements for Alzheimer's Amyloidogenesis

• Published in: Journal of the American Chemical Society Vol. 127; no. 44; pp. 15366 - 15367
• Main Authors: Fu, Yanwen, Bieschke, Jan, Kelly, Jeffery W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.11.2005; Amer Chemical Soc
• Subjects: Alkenes - chemistry; Alzheimer Disease; Aminoacids, peptides. Hormones. Neuropeptides; Amyloid beta-Peptides - biosynthesis; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Chemistry; Chemistry, Multidisciplinary; Dipeptides - chemistry; Fundamental and applied biological sciences. Psychology; Hydrogen Bonding; Molecular Mimicry; Peptides - chemical synthesis; Physical Sciences; Proteins; Science & Technology; PEPTIDE-BOND; (E)-ALKENE; PROLINE; DISEASE; Stereoselectivity; Atomic force microscopy; Biochemical analysis; β Amyloid protein; Secondary structure; Fluorescence microscopy; Aminoacid sequence; Structural analysis; Hydrogen bond
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0551382

Herein, we report a stereospecific E-olefin dipeptide isostere synthesis that can be used to make gram quantities of the Phe−Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Aβ peptide. The Phe19−Phe20 E-olefin analogue of Aβ(1−40) was prepared by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This analogue can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis.