De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach.

ABSTRACT: Protein-protein interactions stabilized by multiple separate hot spots are highly challenging targets for synthetic scaffolds. Surface-mimetic foldamers bearing multiple recognition segments are promising candidate inhibitors. In this work, a modular bottom-up approach is implemented by identifying short foldameric recognition segments that interact with the independent hot spots, and connecting them through dynamic covalent library (DCL) optimization. The independent hot spots of a model target (calmodulin) are mapped with hexameric β-peptide helices using a pull-down assay. Recognition segment hits are subjected to a target-templated DCL ligation through thiol-disulfide exchange. The most potent derivative displays low nanomolar affinity towards calmodulin and effectively inhibits the ca

SUBMITTER: Bartus E 

PROVIDER: S-EPMC5390796 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature