辅活化剂
癌症研究
连环蛋白
信号转导
磷酸化
小分子
作者
Mathias Wendt,Rosa Bellavita,Alan Gerber,Nina Louisa Efrém,Thirza van Ramshorst,Nicholas M Pearce,Paul R. J. Davey,Isabel Everard,Mercedes Vazquez-Chantada,Elisabetta Chiarparin,Paolo Grieco,Sven Hennig,Tom N. Grossmann
标识
DOI:10.1002/anie.202102082
摘要
Protein complexes are defined by the three-dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein-protein interactions (PPIs). Even though β-sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure-based design of β-sheet mimetics targeting the intracellular protein β-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β-catenin, a macrocyclic peptide was designed and its crystal structure in complex with β-catenin obtained. Using this structure, we designed a library of bicyclic β-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β-catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β-sheet-mediated PPIs.
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