Istituto di Cristallografia - CNR

Understanding the interaction between amyloid-?-peptide (1-42) and its aggregation inhibitors: application of ESI and MALDI mass spectrometry

Neurodegenerative disorders (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases are some of the most common forms of age-related diseases. Even if pathogenesis of these neurodegenerative diseases remains unclear, increasing evidences point out a common critical molecular process involving the assembly of various aggregated protein with a ?-sheet conformation, termed amyloids. The inhibition of this process could be a viable therapeutic strategy for the treatment of neurodegenerative diseases. Peptide based inhibitors of ?-amyloid fibrillation are emerging as safe drug candidates as well as interesting compounds for early diagnosis of AD. Some papers in the past reported that the KLVFF peptide, by binding the homologous sequence in full- length A?, can prevent at aggregation into fibrils and this ability is maintained after conjugation to different scaffold.
One of the main hindrances in amyloid protein investigation concerns the low peptide solubility. In this contest, the high sensitivity of mass spectrometry may overcome this limit. Besides measuring the m/z, mass spectrometry enables the identification of adducts formation and it can be used to obtain direct evidence of the interaction between A?(1-42) and its aggregation inhibitors. Despite these informations were deduced from the gas-phase system, the results observed support what can be observed in solution by limited proteolysis experiments. In particular, the identification of proteolysis resistant peptides fragments by mass spectrometry can reveal the binding regions of A?(1-42) to specific molecules in solution.
Here we report two different mass spectrometry approaches to investigate the interaction of A?(1-42) monomer with aggregation inhibitors that we recently studied. In particular, high resolution mass spectrometry (HR-MS) was employed to point out direct interaction of the p-amino-calix[4]arene-GPGKLVFF conjugate with the A?(1-42) monomer.[5] We resorted to limited proteolysis experiments to investigate, by means of MALDI-TOF, the interaction of A?(1-42) with chimera peptides ?9-16-KL and ?26-33-KL and KLVFF.[6]

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Giuseppe Di Natale, Rita Tosto, Grazia Maria Letizia Consoli, Giuseppe Pappalardo
Autori IC CNR
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