Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17-21 beta-amyloid sequence.
Peptide derivatives 1-5, incorporating synthetic non-proteinogenic amino acids, related to the beta-amyloid 17-21 fragment of the amyloidogenic Abeta(1-40), and the N-protected decapeptide 6, corresponding to a dimeric sequence of the same fragment, have been synthesized. These compounds were designed by using Soto's pentapeptide Ac-LPFFD-NH(2) (iAbeta5p) as lead compound. Their activity as inhibitors of fibrillogenesis and stability against enzymatic degradation have been determined. Compounds 1, 5 and 6 are potent inhibitors in comparison to the lead compound. Exposure to chymotrypsin of peptide derivatives 1-5, all containing unnatural amino acids, shows increased stability as compared with iAbeta5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.
Giordano
Cesare
C
Istituto di Chimica Biomolecolare del CNR, Università La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. cesare.giordano@uniroma1.it
Masi
Annalisa
A
Pizzini
Aldo
A
Sansone
Anna
A
Consalvi
Valerio
V
Chiaraluce
Roberta
R
Lucente
Gino
G
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments