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000906017 1001_ $$0P:(DE-Juel1)165176$$aMargreiter, Michael A$$b0
000906017 245__ $$aSmall-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death
000906017 260__ $$aGotenburg$$bResearch Network of Computational and Structural Biotechnology (RNCSB)$$c2022
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000906017 520__ $$aPolyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in Drosophila melanogaster. This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans. Computer-aided drug discovery was implemented to identify human TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined, and Biacore experiments with the RRM were performed. The identified molecules were validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Our work provides a first step towards pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.
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000906017 7001_ $$0P:(DE-HGF)0$$aWitzenberger, Monika$$b1
000906017 7001_ $$0P:(DE-HGF)0$$aWasser, Yasmine$$b2
000906017 7001_ $$0P:(DE-HGF)0$$aDavydova, Elena$$b3
000906017 7001_ $$0P:(DE-HGF)0$$aJanowski, Robert$$b4
000906017 7001_ $$0P:(DE-HGF)0$$aMetz, Jonas$$b5
000906017 7001_ $$0P:(DE-HGF)0$$aHabib, Pardes$$b6
000906017 7001_ $$0P:(DE-HGF)0$$aSahnoun, Sabri E. M.$$b7
000906017 7001_ $$0P:(DE-HGF)0$$aSobisch, Carina$$b8
000906017 7001_ $$0P:(DE-HGF)0$$aPoma, Benedetta$$b9
000906017 7001_ $$0P:(DE-HGF)0$$aPalomino-Hernandez, Oscar$$b10
000906017 7001_ $$0P:(DE-HGF)0$$aWagner, Mirko$$b11
000906017 7001_ $$0P:(DE-HGF)0$$aCarell, Thomas$$b12
000906017 7001_ $$0P:(DE-Juel1)131794$$aShah, N. J.$$b13$$ufzj
000906017 7001_ $$0P:(DE-Juel1)171786$$aSchulz, Jörg B.$$b14$$ufzj
000906017 7001_ $$0P:(DE-HGF)0$$aNiessing, Dierk$$b15
000906017 7001_ $$0P:(DE-HGF)0$$aVoigt, Aaron$$b16
000906017 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b17$$eCorresponding author$$ufzj
000906017 773__ $$0PERI:(DE-600)2694435-2$$a10.1016/j.csbj.2021.12.029$$gVol. 20, p. 443 - 458$$p443 - 458$$tComputational and structural biotechnology journal$$v20$$x2001-0370$$y2022
000906017 8564_ $$uhttps://juser.fz-juelich.de/record/906017/files/Invoice_OAD0000177738.pdf
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