Disulfide-rich, cyclic peptides from Clitoria ternatea protect against β-amyloid toxicity and oxidative stress in transgenic Caenorhabditis elegans

Abstract

Neurotoxic aggregation of β-amyloid (Aβ) peptide is a hallmark of Alzheimer’s disease and increased reactive oxygen species (ROS) is known to be associated with this. Here, we report neuroprotective effects of disulfide-rich, circular peptides from Clitoria ternatea on Aβ-induced toxicity in transgenic Caenorhabditis elegans. We show that cyclotide-rich fractions from different plant tissues delay Aβ-induced paralysis in transgenic CL4176 strain expressing human musclespecific Aβ1–42 gene. It also improved Aβ-induced defects in chemotaxis in CL2355 expressing Aβ1-42 in neuronal cells. ROS assay suggests that this is likely mediated by inhibition of Aβ oligomerization. Further, Aβ deposits were reduced in the strain, CL2006 treated with the fractions. Computational docking and molecular dynamics (MD) simulation support the findings since cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. MD simulation further shows that cyclotides destabilize toxic amyloid assemblies. The study shows that cyclotides from C. ternatea could be a source of novel pharmacophore scaffold against neurodegenerative diseases.