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Open AccessArticle

Tryptophan-Containing Dual Neuroprotective Peptides: Prolyl Endopeptidase Inhibition and Caenorhabditis elegans Protection from β-Amyloid Peptide Toxicity

1
Department of Biotechnology, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), 46980 Paterna, Valencia, Spain
2
Department of Food Biotechnology; Biópolis S.L.-Archer Daniels Midland, Parc Científic Universitat de València Edif. 2, 46980 Paterna, Valencia, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(5), 1491; https://doi.org/10.3390/ijms19051491
Received: 16 April 2018 / Revised: 9 May 2018 / Accepted: 14 May 2018 / Published: 16 May 2018
(This article belongs to the Special Issue Peptides for Health Benefits)
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 β-amyloid peptide (Aβ) 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 Aβ-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 Aβ 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 Aβ oligomerization and thus, amyloid deposition. In conclusion, novel natural and rationally-designed W-containing peptides are suitable starting leads to design effective neuroprotective agents. View Full-Text
Keywords: neurodegenerative diseases; amyloid β peptide; Caenorhabditis elegans; prolyl endopeptidase inhibition; lactoferrin-derived peptides; rationally-designed peptides; tryptophan; molecular docking neurodegenerative diseases; amyloid β peptide; Caenorhabditis elegans; prolyl endopeptidase inhibition; lactoferrin-derived peptides; rationally-designed peptides; tryptophan; molecular docking
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MDPI and ACS Style

Manzanares, P.; Martínez, R.; Garrigues, S.; Genovés, S.; Ramón, D.; Marcos, J.F.; Martorell, P. Tryptophan-Containing Dual Neuroprotective Peptides: Prolyl Endopeptidase Inhibition and Caenorhabditis elegans Protection from β-Amyloid Peptide Toxicity. Int. J. Mol. Sci. 2018, 19, 1491.

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