Human Serum Albumin-Inspired Glycopeptide-Based Multifunctional Inhibitor of Amyloid-β Toxicity

[Image: see text] In Alzheimer’s disease (AD), insoluble Aβ42 peptide fragments self-aggregate and form oligomers and fibrils in the brain, causing neurotoxicity. Further, the presence of redox-active metal ions such as Cu(2+) enhances the aggregation process through chelation with these Aβ42 aggregates as well as generation of Aβ42-mediated reactive oxygen species (ROS). Herein, we have adopted a bioinspired strategy to design and develop a multifunctional glycopeptide hybrid molecule (Glupep), which can serve as a potential AD therapeutic. This molecule consists of a natural metal-chelating tetrapeptide motif of human serum albumin (HSA), a β-sheet breaker peptide, and a sugar moiety for better bioavailability. We performed different biophysical and docking experiments, which revealed that Glupep not only associates with Aβ42 but also prevents its self-aggregation to form toxic oligomers and fibrils. Moreover, Glupep was also shown to sequester out Cu(2+) from the Aβ–Cu(2+) complex, reducing the ROS formation and toxicity. Besides, this study also revealed that Glupep could protect PC12-derived neurons from Aβ–Cu(2+)-mediated toxicity by reducing intracellular ROS generation and stabilizing the mitochondrial membrane potential. All these exciting features show Glupep to be a potent inhibitor of Aβ42-mediated multifaceted toxicity and a prospective therapeutic lead for AD.