Autor(en): | Kunig, Verena B. K. Potowski, Marco Akbarzadeh, Mohammad Škopić, Mateja Klika Santos Smith, Denise dos Arendt, Lukas Dormuth, Ina Adihou, Hélène Andlovic, Blaž Karatas, Hacer Shaabani, Shabnam Zarganes-Tzitzikas, Tryfon Neochoritis, Constantinos G. Zhang, Ran Groves, Matthew Guéret, Stéphanie M. Ottmann, Christian Rahnenführer, Jörg Fried, Roland Dömling, Alexander Brunschweiger, Andreas |
Titel: | TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics |
Sprache (ISO): | en |
Zusammenfassung: | DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors. |
Schlagwörter: | Combinatorial chemistry DNA-encoded library Peptidomimetics Protein–protein interaction inhibition Ugi reaction |
URI: | http://hdl.handle.net/2003/40334 http://dx.doi.org/10.17877/DE290R-22209 |
Erscheinungsdatum: | 2020-06-14 |
Rechte (Link): | https://creativecommons.org/licenses/by/4.0/ |
Enthalten in den Sammlungen: | Chemische Biologie |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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anie.202006280.pdf | 2.63 MB | Adobe PDF | Öffnen/Anzeigen |
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