NR AKAK
AU Rijkers,D.T.; Hoppener,J.W.; Posthuma,G.; Lips,C.J.; Liskamp,R.M.
TI Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides
QU Chemistry (Weinheim an der Bergstrasse, Germany) 2002 Sep 16; 8(18): 4285-91
PT journal article
AB Amyloid deposits are formed as a result of uncontrolled aggregation of (poly)peptides or proteins. Today several diseases are known, for example Alzheimer's disease, Creutzfeldt-Jakob disease, mad cow disease, in which amyloid formation is involved. Amyloid fibrils are large aggregates of beta-pleated sheets and here a general method is described to introduce molecular mutations in order to achieve disruption of beta-sheet formation. Eight backbone-modified amylin derivatives, an amyloidogenic peptide involved in maturity onset diabetes, were synthesized. Their beta-sheet forming properties were studied by IR spectroscopy and electron microscopy. Modification of a crucial amide NH by an alkyl chain led to a complete loss of the beta-sheet forming capacity of amylin. The resulting molecular mutated amylin derivative could be used to break the beta-sheet thus retarding beta-sheet formation of unmodified amylin. Moreover, it was found that the replacement of this amide bond by an ester moiety suppressed fibrillogenesis significantly. Introduction of N-alkylated amino acids and/or ester functionalities-leading to depsipeptides-into amyloidogenic peptides opens new avenues towards novel peptidic beta-sheet breakers for inhibition of beta-amyloid aggregation.
AD Department of Medicinal Chemistry Utrecht Institute for Pharmaceutical Sciences Faculty of Pharmaceutical Sciences Utrecht University, P.O. Box 80082 3508 TB Utrecht, The Netherlands.
SP englisch
PO Deutschland