Peptoid-Peptide Macrocycles Inhibit Wnt Signaling
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Solution Overview
Problem
Current therapies for prostate cancer and other diseases related to aberrant Wnt signaling pathway activity are limited by resistance mechanisms and lack of effective inhibitors for protein-protein interactions.
Innovation Solution
Development of peptoid-containing macrocycles, specifically peptoid-peptide macrocycles, that can inhibit the Wnt signaling pathway by targeting the interaction between β-catenin and TCF, thereby offering a novel approach to treating cancers and hyperproliferative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If small molecules are used to inhibit protein-protein interactions, then binding specificity may be achieved, but binding strength is insufficient due to lack of surface area
Solution Approach 1:
The patent merges peptoid and peptide components into a hybrid macrocycle structure that combines the binding specificity of peptoids with the binding strength of peptides. The peptoid portion provides conformational stability and specificity through its rigid backbone, while the peptide portion contributes binding strength through extended surface area contact with the protein target.
Solution Approach 2:
The invention creates a composite molecular structure combining peptoid and peptide units within a single macrocycle. This composite approach allows the molecule to exhibit both the conformational order and binding specificity of peptoids and the surface area and binding strength of peptides, resolving the contradiction between specificity and strength.
2Area of stationary object
If peptides are used to target protein-protein interactions, then binding surface area is sufficient, but pharmacological characteristics are poor and degradation susceptibility increases
Solution Approach 1:
The peptoid component acts as an intermediary structure that provides conformational stability and proteolytic resistance to the hybrid macrocycle. This intermediary peptoid backbone protects the peptide portion from degradation while allowing the peptide to maintain its binding surface area and pharmacological activity.
Solution Approach 2:
The patent changes the structural parameters of the molecule by incorporating peptoid units with rigid backbones and specific side chain configurations. This parameter change enhances conformational stability and resistance to degradation while maintaining the binding surface area through the peptide component.
3Stability of the object's composition
If peptoids are used to inhibit PPIs, then conformational stability is improved, but binding surface area is insufficient
Solution Approach 1:
The patent segments the macrocycle into distinct peptoid and peptide segments, where the peptoid segment provides conformational stability through its rigid backbone and the peptide segment provides binding surface area through its extended structure. This segmentation allows each component to optimize its function without compromising the other.
Solution Approach 2:
The hybrid macrocycle is a composite structure where peptoid and peptide units work together: the peptoid portion ensures conformational stability and structural order, while the peptide portion extends the binding surface area to achieve sufficient interaction with the protein target.
4Productivity
If linear peptoid sequences are used, then synthesis efficiency is high, but conformational heterogeneity reduces binding predictability
Solution Approach 1:
The patent merges linear peptoid synthesis efficiency with macrocyclic conformational constraint. The linear peptoid backbone maintains synthesis efficiency through standard solid-phase synthesis methods, while the macrocyclization step imposes conformational order that enhances binding predictability by reducing conformational heterogeneity.
Solution Approach 2:
The transition from linear to macrocyclic structure represents a phase change in conformational space. This macrocyclization phase transition reduces conformational heterogeneity by constraining the peptoid chain into a defined three-dimensional structure, thereby improving binding predictability while maintaining synthesis efficiency.
Data Source
AI summary
Provided are peptoid-peptide macrocycles. The peptoid-peptide macrocycles may have inhibitory activity towards the Wnt signaling pathway. The Wnt signaling pathway is associated with cancer and other diseases and conditions. Such diseases include, for example, pulmonary fibrosis. Also described are methods of making the peptoid-peptide macrocycles, compositions containing the peptoid-peptide macrocycles, and methods of using the peptoid-peptide macrocycles.