Screening Platform Based on Inductively Coupled Plasma Mass Spectrometry for β-Site Amyloid Protein Cleaving Enzyme 1...

β-Site amyloid protein cleaving enzyme 1 (BACE1) is a promising therapeutic target for developing inhibitors to alleviate Alzheimer's disease (AD). Herein, we established an inductively coupled plasma mass spectrometry (ICPMS)-based inhibitor screening platform. A biotin-labeled lanthanide-coded peptide probe (LCPP; biotin-PEG₂-EVNLDAEC-DOTA-Ln) was designed to determine the activity of BACE1 and evaluate the degree of inhibition of inhibitors. The platform was first validated with two commercially available inhibitors (BSI I and BSI IV) in terms of IC₅₀ values and then applied to two newly designed inhibitors (inhibitors II and III) based on the crystal structure of BACE1 interacting with inhibitor I, and each of them contained an acylguanidine core structure. We found that their inhibition effects were improved as evaluated by the sensitive and accurate LCPP-ICPMS platform, demonstrating its ability for new drug screening.