Chimeric Proteins with Repeat Domain Scaffolds for PPI Targeting

The patent introduces chimeric proteins as intermediary molecules that mediate PPI inhibition. These chimeric proteins comprise a scaffold domain (derived from repeat proteins like TPR, ankyrin, or helical bundles) and a peptide ligand domain, allowing them to bind to PPI targets with high affinity and specificity. This intermediary approach overcomes the limitations of conventional small molecules by providing a customizable, high-affinity binding interface that can be tailored to specific PPI targets, thereby expanding the druggable proteome while maintaining reliable inhibition effectiveness.

The patent applies segmentation by dividing the chimeric protein into distinct functional modules: a scaffold domain comprising repeat units (TPR, ankyrin, or helical bundles) and a peptide ligand domain. Each module can be independently designed, optimized, and characterized. The scaffold provides structural stability through its repeat domain architecture, while the peptide ligand provides target-specific binding functionality. This modular segmentation allows for systematic construction of chimeric proteins with desired properties, managing complexity through standardized module assembly rather than de novo protein design.

The patent implements multi-functionality by incorporating multiple peptide ligands into a single scaffold domain. Each peptide ligand can be designed to bind to different targets or perform different functions (e.g., target binding, E3 ligase recruitment, degradation signaling). The scaffold serves as a universal platform that can accommodate various ligand combinations, enabling a single chimeric protein to perform multiple functions simultaneously. This approach expands therapeutic versatility while managing design complexity through a standardized scaffold architecture that provides a consistent framework for ligand integration.