Tryptophan-Containing Dual Neuroprotective Peptides: Prolyl Endopeptidase Inhibition and Caenorhabditis elegans Protection from ß-Amyloid Peptide Toxicity.
Int J Mol Sci
; 19(5)2018 May 16.
Article
em En
| MEDLINE
| ID: mdl-29772745
ABSTRACT
Neuroprotective peptides represent an attractive pharmacological strategy for the prevention or treatment of age-related diseases, for which there are currently few effective therapies. Lactoferrin (LF)-derived peptides (PKHs) and a set of six rationally-designed tryptophan (W)-containing heptapeptides (PACEIs) were characterized as prolyl endopeptidase (PEP) inhibitors, and their effect on ß-amyloid peptide (Aß) toxicity in a Caenorhabditis elegans model of Alzheimer's disease (AD) was evaluated. Two LF-derived sequences, PKH8 and PKH11, sharing a W at the C-terminal end, and the six PACEI heptapeptides (PACEI48L to PACEI53L) exhibited significant in vitro PEP inhibition. The inhibitory peptides PKH11 and PACEI50L also alleviated Aß-induced paralysis in the in vivo C. elegans model of AD. Partial or total loss of the inhibitory effect on PEP was achieved by the substitution of W residues in PKH11 and PACEI50L and correlated with the loss of protection against Aß toxicity, pointing out the relevance of W on the neuroprotective activity. Further experiments suggest that C. elegans protection might not be mediated by an antioxidant mechanism but rather by inhibition of Aß oligomerization and thus, amyloid deposition. In conclusion, novel natural and rationally-designed W-containing peptides are suitable starting leads to design effective neuroprotective agents.
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MEDLINE
Assunto principal:
Neuropeptídeos
/
Peptídeos beta-Amiloides
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article