Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling

Abstract

Protein complexes are defined by the three-dimensional structure of participating binding partners.K nowledge about these structures can facilitate the design of peptidomimetics which have been applied for example,a si nhibitors of protein-protein interactions (PPIs). Even though b-sheets participate widely in PPIs,t hey have only rarely served as the basis for peptidomimetic PPI inhibitors,inparticular when addressing intracellular targets.Here,wepresent the structurebased design of b-sheet mimetics targeting the intracellular protein b-catenin, ac entral component of the Wnt signaling pathway.B ased on ap rotein binding partner of b-catenin, amacrocyclic peptide was designed and its crystal structure in complex with b-catenin obtained. Using this structure,w e designed al ibrary of bicyclic b-sheet mimetics employing al ate-stage diversification strategy.S everal mimetics were identified that compete with transcription factor binding to bcatenin and inhibit Wnt signaling in cells.The presented design strategy can support the development of inhibitors for other bsheet-mediated PPIs.

Protein Macrocyclization for Tertiary Structure Stabilization

“…The presented cyclic proteins have mainly found application as biocatalysts or ligands for cellular receptors. There is growing evidence that stabilized tertiary structures can also allow the inhibition of protein‐protein interactions[ 90 , 91 , 92 , 93 ] that are not addressable with classic peptidomimetic approaches. [ 94 , 95 ] Therefore, it can be expected that cyclic proteins will find more fields of application in the future.…”

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

“…They are designed to mimic the 3D structures of the original PPI binding partners or segments and further compete with them for PPI disruption. Peptidomimetics usually mimic specific PPI interfacial structures such as α- helixes or β-sheets (Wendt et al, 2021 ), and the addition of functional modifications toward the lead peptide templates can enormously enhance their potency and efficacy. Relative to natural peptides, introduction of medicinal chemical functional groups or artificial pharmacological structures can substantially enhance their inhibitory activity as well as bypass the intrinsic limitations such as poor proteolysis stability or compromised bioavailability (Qvit et al, 2017 ).…”

Leucine rich repeat kinase 2 (LRRK2) peptide modulators: Recent advances and future directions

“…Previous efforts to develop beta sheet mimetics have yielded a library of selective, high affinity binders. [ 117–119 ] Parallel approaches could be utilized to design a COR‐targeting dimerization disruptor for LRRK2. Alternatively, the N‐terminal region of LRRK2 was also shown to contribute to dimerization in the full‐length dimer structure, but these domains are primarily helical.…”