Abstract
Inhibition of the initial stages of amyloid-beta peptide self-assembly is a key approach in drug development for Alzheimer's disease, in which soluble and highly neurotoxic low molecular weight oligomers are produced and aggregate in the brain over time. Here we report a high-throughput method based on ion mobility mass spectrometry and multivariate statistical analysis to rapidly select statistically significant early-stage species of amyloid-beta 1-40 whose formation is inhibited by a candidate theranostic agent. Using this method, we have confirmed the inhibition of a Zn-porphyrin-peptide conjugate in the early self-assembly of A beta 40 peptide. The MS/MS fragmentation patterns of the species detected in the samples containing the Zn-porphyrin-peptide conjugate suggested a porphyrin-catalyzed oxidation at Met-35(O) of A beta 40. We introduce ion mobility MS combined with multivariate statistics as a systematic approach to perform data analytics in drug discovery/amyloid research that aims at the evaluation of the inhibitory effect on the A beta early assembly in vitro models at very low concentration levels of A beta peptides.
Original language | English |
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Pages (from-to) | 6353-6363 |
Number of pages | 11 |
Journal | Analytical and Bioanalytical Chemistry |
Volume | 411 |
Issue number | 24 |
DOIs | |
Publication status | Published - Sept 2019 |
Keywords
- Alzheimer's disease (AD)
- Amyloid beta-peptide oligomers
- Electrospray ionization-ion mobility-mass spectrometry (ESI-IM-MS)
- Multivariate statistical analysis (MVA)
- AMYLOID-BETA-PROTEIN
- MASS-SPECTROMETRY
- NEURODEGENERATIVE DISEASES
- PERSONALIZED MEDICINE
- OXIDATION
- POLYMORPHISM
- AGGREGATION
- INHIBITORS
- STRATEGIES
- OLIGOMERS