Large transition state stabilization from a weak hydrogen bond.
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ABSTRACT:
SUBMITTER: Vik EC
PROVIDER: S-EPMC8159443 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Peptide secondary and tertiary structure motifs frequently serve as inspiration for the development of protein-protein interaction (PPI) inhibitors. While a wide variety of strategies have been used to stabilize or imitate ?-helices, similar strategies for ?-sheet stabilization are more limited. Synthetic scaffolds that stabilize reverse turns and cross-strand interactions have provided important insights into ?-sheet stability and folding. However, these templates occupy regions of the ?-sheet that might impact the ?-sheet's ability to bind at a PPI interface. Here, we present the hydrogen bond surrogate (HBS) approach for stabilization of ?-hairpin peptides. The HBS linkage replaces a cross-strand hydrogen bond with a covalent linkage, conferring significant conformational and proteolytic resistance. Importantly, this approach introduces the stabilizing linkage in the buried ?-sheet interior, retains all side chains for further functionalization, and allows efficient solid-phase macrocyclization. We anticipate that HBS stabilization of PPI ?-sheets will enhance the development of ?-sheet PPI inhibitors and expand the repertoire of druggable PPIs.
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