E-olefin dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer's amyloidogenesis.
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 Abeta peptide. The Phe19-Phe20 E-olefin analogue of Abeta(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.
Fu
Yanwen
Y
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC 506, La Jolla, CA 92037, USA.
Bieschke
Jan
J
Kelly
Jeffery W
JW
D000475:Alkenes / Q000737:chemistry*; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D004151:Dipeptides / Q000737:chemistry*; D006860:Hydrogen Bonding; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis*
D000475:Alkenes; D016229:Amyloid beta-Peptides; D004151:Dipeptides; D010455:Peptides