Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene ß-Catenin.
Angew Chem Int Ed Engl
; : e202411749, 2024 Aug 21.
Article
in En
| MEDLINE
| ID: mdl-39167026
ABSTRACT
The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene ßcatenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α-helical ßcatenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a ß-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2024
Document type:
Article
Affiliation country:
Países Bajos
Country of publication:
Alemania