Novel Peptide-Calix[4]arene Conjugate Inhibits Aβ Aggregation and Rescues Neurons from Aβ's Oligomers Cytotoxicity In Vitro

Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting people in the elderly. Targeting aggregation of beta-amyloid peptides (A beta) is considered a promising approach for the therapeutic treatment of the disease. Peptide based inhibitors of beta-amyloid fibrillation are emerging as safe drug candidates as well as interesting compounds for early diagnosis of AD. Peptide conjugation via covalent bond with functional moieties enables the resultant hybrid system to acquire desired functions. Here we report the synthesis, the structural characterization, and the A beta(42) interaction of a p-amino-calix[4]arene derivative bearing a GPGKLVFF peptide pendant at the lower rim. We demonstrate that the p-amino-calix[4]arene-GPGKLVFF conjugate alters the A beta(42) aggregation pathways by preventing A beta(42)'s conformational transition from random coil to beta-sheet with concomitant changes of the aggregation kinetic profile as evidenced by circular dichroism (CD), thioflavin T (ThT), and dynamic light scattering (DLS) measurements, respectively. High resolution mass spectrometry (HR-MS) confirmed a direct interaction of the p-amino-calix[4]arene-GPGKLVFF conjugate with A beta(42) monomer which provided insight into a possible working mechanism, whereas the alteration of the A beta(42)'s fibrillary architecture, by the calix-peptide conjugate, was further validated by atomic force microscopy (AFM) imaging. Finally, the herein proposed compound was shown to be effective against A beta(42) oligomers' toxicity in differentiated neuroblastoma cells, SH-SY5Y.

Automated summary

Alzheimer's disease is a progressive neurodegenerative condition affecting the elderly, and targeting beta-amyloid peptides aggregation is considered a promising therapeutic approach. Peptide-based inhibitors are emerging as safe drug candidates and interesting compounds for early diagnosis of AD, with the ability to alter the aggregation pathways and architectural changes of beta-amyloid fibrils.