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

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 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.

Disulfide-rich, cyclic peptides fromClitoria ternateaprotect against β-amyloid toxicity and oxidative stress in transgenicCaenorhabditis elegans

“…The lower doses of CRF tested (20 and 80 μg/ml) produced less significant protective effects, however, the highest dose tested (200 μg/ml) delayed the paralysis phenotype drastically compared to the untreated and positive controls. Many compounds such as scorpion venom peptides 22 , sesamin and sesamolin 42 , and tryptophan-containing heptapeptides 24 exert protective effects against Aβ toxicity tested using the same strain of C. elegans . With the development of newer transgenic C. elegans models, Aβ expression has been made to express pan-neuronally 43 .…”

“…Peptides have few advantages over small molecules due to their low-toxicity, non-immunogenicity, better bioavailability and convenient synthesis 19,20 . However, studies on neuroprotection by peptides against Aβ toxicity are limited 6,21–24 .…”

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity

“…Tryptophan derivatives have been employed in the design of several inhibitors of amyloid formation. For example, tryptophan-containing peptides have been employed to reduce Aβ42-derived toxicity in animal models 81 . Tryptophan-coated gold and silver nanoparticles have been shown to inhibit both spontaneous and seed-induced aggregation of insulin 82 .…”

Effect of Peptides Synthesized From Lactoferrin of Buffalo Milk on Oxidative Stress in Kunming Mice

“…Also, tryptophan at the c-terminal plays an important role as an antioxidant and angiotensinconverting enzyme (ACE) inhibitory activities for this peptides. In addition, SVDGKEDLIW inhibited prolyl endopeptidase (PEP) in a Caenorhabditis elegans model of Alzheimer's disease (Manzanares et al, 2018).…”