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

Computational and Structural Biotechnology Journal

N. Jon Shah¹  Monika Witzenberger¹  Giulia Rossetti²  Carina Sobisch³  Jörg B. Schulz⁴  Dierk Niessing⁴  Elena Davydova⁵  Mirko Wagner⁵  Sabri E.M. Sahnoun⁵  Oscar Palomino-Hernandez⁵  Benedetta Poma⁶  Jonas Metz⁷  Yasmine Wasser⁷  Robert Janowski⁷  Michael A Margreiter⁸  Pardes Habib⁸  Thomas Carell⁸  Aaron Voigt⁹ 

[1] Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, 52425 Aachen, Germany;Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Juelich GmbH, Germany;JARA - BRAIN - Translational Medicine, Aachen, Germany;Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany;Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany;Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany;Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Structural Biology, 85764 Neuherberg, Germany;Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany;JARA - BRAIN - Translational Medicine, Aachen, Germany;

关键词: PolyQ;    TRMT2A;    Computer-aided drug discovery;    RNA recognition motif;    Aggregation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown