Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting people in the elderly. Targeting aggregation of β-amyloid peptides (Aβ) is considered a promising approach for the therapeutic treatment of the disease. Peptide based inhibitors of β-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 Aβ42 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 Aβ42 aggregation pathways by preventing Aβ42's conformational transition from random coil to β-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 Aβ42 monomer which provided insight into a possible working mechanism, whereas the alteration of the Aβ42'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 Aβ42 oligomers' toxicity in differentiated neuroblastoma cells, SH-SY5Y.
Keywords: Aβ oligomers; SH-SY5Y cells; amyloid; calixarenes; peptides.