Ion mobility spectrometry combined with multivariate statistical analysis: revealing the effects of a drug candidate for Alzheimer's disease on A?1-40 peptide early assembly

Inhibition of the initial stages of amyloid-? 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-?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?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?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? early assembly in vitro models at very low concentration levels of A? peptides.

Attività antifibrillogenica di un peptide coniugato con uno scaffold porfirinico. Studio di spettrometria di massa con tecnica ion mobility accoppiata ad una analisi statistica multivariata delle forme oligomeriche di amiloide beta osservate.