Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity

We described herein structure-based design, synthesis and evaluation of conformationally constrained, cyclic peptidomimetics to block the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 histone methyltransferase activity. Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5 (Ki values <1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.

Graphical abstractStructure-based design, synthesis and evaluation of high-affinity, conformationally constrained peptidomimetics as inhibitors of the WDR5-MLL1 protein–protein interaction and MLL1 methyltransferase activity are described.Figure optionsDownload full-size imageDownload as PowerPoint slide