Journal of Medicinal Chemistry p. 6121 - 6139 (2018)
Update date:2022-08-15
Topics:
Karch, Sandra
Broichhagen, Johannes
Schneider, Julia
B?ning, Daniel
Hartmann, Stephanie
Schmid, Benjamin
Tripal, Philipp
Palmisano, Ralf
Alzheimer, Christian
Johnsson, Kai
Huth, Tobias
β-site APP-cleaving enzyme 1 (BACE1) is a major player in the pathogenesis of Alzheimer's disease. Structural and functional fluorescence microscopy offers a powerful approach to learn about the physiology and pathophysiology of this protease. Up to now, however, common labeling techniques require genetic manipulation, use large antibodies, or are not compatible with live cell imaging. Fluorescent small molecules that specifically bind to the protein of interest can overcome these limitations. Herein, we introduce SiR-BACE1, a conjugate of the BACE1 inhibitor S-39 and SiR647, as a novel fluorogenic, tag-free, and antibody-free label for BACE1. We present its chemical development, characterize its photophysical and pharmacologic properties, and evaluate its behavior in solution, in overexpression systems, and in native brain tissue. We demonstrate its applicability in confocal, stimulated emission depletion and dynamic single-molecule microscopy. The first functional studies with SiR-BACE1 on the surface mobility of BACE1 revealed a markedly confined diffusion pattern.
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