Retro-enantio N-methylated peptides as beta-amyloid aggregation inhibitors.
An emerging and attractive target for the treatment of Alzheimer's disease is to inhibit the aggregation of beta-amyloid protein (Abeta). We applied the retro-enantio concept to design an N-methylated peptidic inhibitor of the Abeta42 aggregation process. This inhibitor, inrD, as well as the corresponding all-L (inL) and all-D (inD) analogues were assayed for inhibition of Abeta42 aggregation. They were also screened in neuroblastoma cell cultures to assess their capacity to inhibit Abeta42 cytotoxicity and evaluated for proteolytic stability. The results reveal that inrD and inD inhibit Abeta42 aggregation more effectively than inL, that inrD decreases Abeta42 cytotoxicity to a greater extent than inL and inD, and that as expected, both inD and inrD are stable to proteases. Based on these results, we propose that the retro-enantio approach should be considered in future designs of peptide inhibitors of protein aggregation.
Grillo-Bosch
Dolors
D
Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
Carulla
Natàlia
N
Cruz
Montse
M
Sánchez
Laia
L
Pujol-Pina
Rosa
R
Madurga
Sergio
S
Rabanal
Francesc
F
Giralt
Ernest
E
D000544:Alzheimer Disease / Q000188:drug therapy; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000633:toxicity; D009842:Oligopeptides / Q000737:chemistry* / Q000633:toxicity; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); C545856:inD peptide; C545855:inL peptide; C545857:inrD peptide