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Margreiter, M.A.* ; Witzenberger, M. ; Wasser, Y.* ; Davydova, E.-O. ; Janowski, R. ; Metz, J.* ; Habib, P.* ; Sahnoun, S.E.M.* ; Sobisch, C.* ; Poma, B.* ; Palomino-Hernández, O.* ; Wagner, M.* ; Carell, T.* ; Jon Shah, N.* ; Schulz, J.B.* ; Niessing, D. ; Voigt, A.* ; Rossetti, G.*

Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death.

Comp. Struc. Biotech. J. 20, 443-458 (2022)
Publ. Version/Full Text Research data DOI PMC
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Polyglutamine (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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Publication type Article: Journal article
Document type Scientific Article
Keywords Aggregation ; Computer-aided Drug Discovery ; Polyq ; Rna Recognition Motif ; Trmt2a
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 2001-0370
e-ISSN 2001-0370
Journal Computational and Structural Biotechnology Journal
Quellenangaben Volume: 20, Issue: , Pages: 443-458 Article Number: , Supplement: ,
Publisher Research Network of Computational and Structural Biotechnology (RNCSB)
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503091-001
Grants Bundesministerium fur Bildung und Forschung (BMBF)
DOI 10.1016/j.csbj.2021.12.029
WOS ID WOS:000819903300015
Scopus ID 85122543614
PubMed ID 35070167
Erfassungsdatum 2022-01-27
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