LAUSR

The aggregation of disordered α-synuclein protein is pathogenically connected with Parkinson's disease. Therefore, discovering molecules that can inhibit the misfolding and aggregation of α-synuclein is an active research area in PD drug development. A key property of such required therapeutic agents is specific binding to the target protein. Mass spectrometry allows rapid detection of direct interactions between molecules and proteins and is an ideal technique for discovering specific α-synuclein binders. Here, by setting up an automated mass spectrometry-based screening system, we were able to screen over 2,500 compounds and identify a new α-synuclein inhibitor, 3-[(3-methoxyphenyl)carbamoyl]-7-[(E)-2-phenylethenyl]-4,7-dihydropyrazolo [1,5-a]pyrimidine-5-carboxylic acid (compound 2). This compound not only significantly inhibited the misfolding and aggregation of α-synuclein, protected neuroblastoma cells from α-synuclein toxicity, but also has a more specific binding site compared with positive controls. Our work for the first time reported the inhibition of compound 2 on α-synuclein aggregation and also consolidated the capability of mass spectrometry to discover α-synuclein aggregation inhibitors.