complete phenotypic recovery of an alzheimers disease model by a quinone-tryptophan hybrid aggregation inhibitor阿尔茨海默病模型的完整的表型复苏quinone-tryptophan混合聚合抑制剂.pdf

Complete Phenotypic Recovery of an Alzheimer’s Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor 1 2 2 1 1 Roni Scherzer-Attali , Riccardo Pellarin , Marino Convertino , Anat Frydman-Marom , Nirit Egoz-Matia , 1 1 3 2 1 1 Sivan Peled , Michal Levy-Sakin , Deborah E. Shalev , Amedeo Caflisch , Ehud Gazit *, Daniel Segal * 1 Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel, 2 Department of Biochemistry, University of Zurich, Zurich, Switzerland, 3 Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, Jerusalem, Israel Abstract The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer’s disease-associated b-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties an