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  • Title: Quercitrin and quercetin 3-β-d-glucoside as chemical chaperones for the A4V SOD1 ALS-causing mutant.
    Author: Ip P, Sharda PR, Cunningham A, Chakrabartty S, Pande V, Chakrabartty A.
    Journal: Protein Eng Des Sel; 2017 Jun 01; 30(6):431-440. PubMed ID: 28475686.
    Abstract:
    In many cases of familial amyotrophic lateral sclerosis (ALS), mutant forms of the Cu,Zn superoxide dismutase protein (SOD1) misfold and aggregate in motor neurons. Monomers of the normally homodimeric SOD1 have been found in patient tissue, presymptomatic mouse models of ALS, and in vitro misfolding assays which suggests that monomerization might be an early step in the pathological SOD1 misfolding pathway. In this study, we targeted the dimer interface with small molecules that might act as chemical chaperones to stabilize the native dimer and prevent downstream misfolding and aggregation. We performed a computational screen with a library of ~4400 drugs and natural compounds that were docked to two pockets around the SOD1 dimer interface. Of the resultant hits, seven were tested for misfolding and aggregation inhibition activity with A4V mutant SOD1. Quercitrin, quercetin-3-β-d-glucoside (Q3BDG), and, to a markedly lesser extent, epigallocatechin gallate (EGCG) were found to combat misfolding and aggregation induced by hydrogen peroxide, a physiologically relevant stress, as assessed by a gel-based assay and 8-anilinonaphthalene-1-suflonic acid (ANS) fluorescence. Isothermal titration calorimetry (ITC) and a colourimetric assay determined that these molecules directly bind A4V SOD1. Based on these findings, we speculate that quercitrin and Q3BDG may be potential therapeutic inhibitors of misfolding and aggregation in SOD1-associated ALS.
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