Identification of Chemical Probes Targeting MBD2
| Autor: | Diane Erdmann, Jean Contreras, Rémy A. Le Meur, Bruno Vitorge, Vincent Saverat, Ambre Tafit, Corinne Jallet, Véronique Cadet-Daniel, Corentin Bon, Phannarath Phansavath, Virginie Ratovelomanana-Vidal, Albert Jeltsch, Sophie Vichier-Guerre, J. Iñaki Guijarro, Paola B. Arimondo |
|---|---|
| Přispěvatelé: | Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, Institute of Chemistry for Life and Health Sciences (iCLeHS), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Stuttgart, The 800-MHz NMR spectrometer of the Institut Pasteur was partially funded by the Région Ile de France (SESAME 2014 NMRCHR grant no. 4014526). The project was financed by the French PPR Antiobioresistance ANR-20-PAMR-0011–TheraEPI (to P.B.A.)., We thank Prof. Srinivasan and Prof. Nelson from the Sidney Kimmel Comprehensive Cancer Center at the University of Medicine, Johns Hopkins (Baltimore, MD) for the kind gift of MBD2-His plasmid. We thank Ludovic Halby for the design of the synthetic pathway and for the fruitful discussions on the project conception., ANR-20-PAMR-0011,TherAEPI,Thérapies épigénétiques pour esquiver la résistance(2020) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | ACS Chemical Biology ACS Chemical Biology, 2022, Published as part of the ACS Chemical Biology special issue “Epigenetics 2022”., 17 (6), pp.1415-1426. ⟨10.1021/acschembio.1c00959⟩ |
| ISSN: | 1554-8929 1554-8937 |
| DOI: | 10.1021/acschembio.1c00959⟩ |
| Popis: | International audience; Epigenetics has received much attention in the past decade. Many insights on epigenetic (dys)regulation in diseases have been obtained, and clinical therapies targeting them are in place. However, the readers of the epigenetic marks are lacking enlightenment behind this revolution, and it is poorly understood how DNA methylation is being read and translated to chromatin function and cellular responses. Chemical probes targeting the methyl-CpG readers, such as the methyl-CpG binding domain proteins (MBDs), could be used to study this mechanism. We have designed analogues of 5-methylcytosine to probe the MBD domain of human MBD2. By setting up a protein thermal shift assay and an AlphaScreen-based test, we were able to identify three fragments that bind MBD2 alone and disrupt the MBD2-methylated DNA interactions. Two-dimensional NMR experiments and virtual docking gave valuable insights into the interaction of the ligands with the protein showing that the compounds interact with residues that are important for DNA recognition. These constitute the starting point for the design of potent chemical probes for MBD proteins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|