Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling

• Published in: ACS chemical neuroscience Vol. 11; no. 22; pp. 3823 - 3837
• Main Authors: Gunesch, Sandra, Soriano-Castell, David, Lamer, Stephanie, Schlosser, Andreas, Maher, Pamela, Decker, Michael
• Format: Journal Article
• Language: English
• Published: American Chemical Society 18.11.2020
• Subjects: natural product hybrids; Alzheimer’s disease; neuroinflammation; CuAAC
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.0c00589

Alzheimer’s disease (AD) is the most common form of dementia, and up to now, there are no disease-modifying drugs available. Natural product hybrids based on the flavonoid taxifolin and phenolic acids have shown a promising pleiotropic neuroprotective profile in cell culture assays and even disease-modifying effects in vivo. However, the detailed mechanisms of action remain unclear. To elucidate the distinct intracellular targets of 7-O-esters of taxifolin, we present in this work the development and application of a chemical probe, 7-O-cinnamoyltaxifolin-alkyne, for target identification using activity-based protein profiling. 7-O-Cinnamoyltaxifolin-alkyne remained neuroprotective in all cell culture assays. Western blot analysis showed a comparable influence on the same intracellular pathways as that of the lead compound 7-O-cinnamoyltaxifolin, thereby confirming its suitability as a probe for target identification experiments. Affinity pulldown and MS analysis revealed adenine nucleotide translocase 1 (ANT-1) and sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) as intracellular interaction partners of 7-O-cinnamoyltaxifolin-alkyne and thus of 7-O-esters of taxifolin.