Snake Venom-Inspired Novel Peptides Protect <i>Caenorhabditis elegans</i> against Paraquat-Induced Parkinson’s Pathology

The <i>in vivo</i> protective mechanisms of two low-molecular-mass (∼1.4 kDa) novel custom peptides (CPs) against paraquat-induced neurodegenerative dysfunction in the <i>Caenorhabditis elegans</i> model were deciphered. CPs prevented the paraquat from binding to the nerve ring adjacent to the pharynx in <i>C. elegans</i> (wild-type) by stable and high-affinity binding to the tyrosine-protein kinase receptor CAM-1, resulting in significant inhibition of paraquat-induced toxicity by reducing the production of reactive oxygen species, mitochondrial membrane depolarization, and chemosensory dysfunction. The CPs inhibited paraquat-induced dopaminergic neuron degeneration and alpha-synuclein protein expression, the hallmarks of Parkinson's disease, in transgenic BZ555 and NL5901 strains of <i>C. elegans</i>. Transcriptomic, functional proteomics, and quantitative reverse transcription-polymerase chain reaction analyses show that CPs prevented the increased expression of the genes involved in the skn-1 downstream pathway, thereby restoring paraquat-mediated oxidative stress, apoptosis, and neuronal damage in <i>C. elegans</i>. The ability of CPs to repair paraquat-induced damage was demonstrated by a network of gene expression profiles, illustrating the molecular relationships between the regulatory proteins.