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000893035 1001_ $$0P:(DE-Juel1)169248$$aSantur, Karoline$$b0
000893035 245__ $$aLigand-Induced Stabilization of the Native Human Superoxide Dismutase 1
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000893035 520__ $$aA common characteristic of familial (fALS) and sporadic amyotrophic lateral sclerosis (sALS) is the accumulation of aberrant proteinaceous species in the motor neurons and spinal cord of ALS patients—including aggregates of the human superoxide dismutase 1 (hSOD1). hSOD1 is an enzyme that occurs as a stable dimeric protein with several post-translational modifications such as the formation of an intramolecular disulfide bond and the acquisition of metal cofactors that are essential for enzyme activity and further contribute to protein stability. Some mutations and/or destabilizing factors promote hSOD1 misfolding, causing neuronal death. Aggregates containing misfolded wild-type hSOD1 have been found in the spinal cords of sALS as well as in non-hSOD1 fALS patients, leading to the hypothesis that hSOD1 misfolding is a common part of the ALS pathomechanism. Therefore, stabilizing the native conformation of SOD1 may be a promising approach to prevent the formation of toxic hSOD1 species and thus ALS pathogenesis. Here, we present the 16-mer peptide S1VL-21 that interferes with hSOD1 aggregation. S1VL-21 was identified by phage display selection with the native conformation of hSOD1 as a target. Several methods such as microscale thermophoresis (MST) measurements, aggregation assays, and cell viability assays revealed that S1VL-21 has a micromolar binding affinity to native hSOD1 and considerably reduces the formation of hSOD1 aggregates. This present work therefore provides the first important data on a potential lead compound for hSOD1-related drug development for ALS therapy.
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000893035 7001_ $$0P:(DE-HGF)0$$aReinartz, Elke$$b1
000893035 7001_ $$0P:(DE-Juel1)179273$$aLien, Yi$$b2
000893035 7001_ $$0P:(DE-Juel1)131709$$aTusche, Markus$$b3
000893035 7001_ $$0P:(DE-Juel1)173052$$aAltendorf, Tim$$b4
000893035 7001_ $$0P:(DE-Juel1)165152$$aSevenich, Marc$$b5
000893035 7001_ $$0P:(DE-Juel1)177986$$aTamgüney, Gültekin$$b6
000893035 7001_ $$0P:(DE-Juel1)132012$$aMohrlüder, Jeannine$$b7$$eCorresponding author
000893035 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b8$$eCorresponding author
000893035 773__ $$0PERI:(DE-600)2528493-9$$a10.1021/acschemneuro.1c00253$$gp. acschemneuro.1c00253$$n13$$p2520–2528$$tACS chemical neuroscience$$v12$$x1948-7193$$y2021
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