期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 46, 页码 20338-20342出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202006280
关键词
combinatorial chemistry; DNA-encoded library; peptidomimetics; protein-protein interaction inhibition; Ugi reaction
资金
- Boehringer Ingelheim foundation exploration grant
- DFG (Deutsche Forschungsgemeinschaft) [BR 5049/3-1]
- Mercator Research Center Ruhr (MERCUR) [Pr-2016-0010]
- EFRE-NRW
- European Union through the TASPPI project (H2020-MSCA-ITN-2015) [675179]
- National Institute of Health (NIH) [2R01GM097082-05]
- COFUND ALERT [665250]
- Hartstichting (ESCAPE-HF) [2018B012]
- KWF Kankerbestrijding grant [10504]
- Max Planck Institute of Molecular Physiology Dortmund
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.
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