Targeted protein degradation is rapidly emerging as a powerful therapeutic approach for eliminating disease-causing proteins in cancer, neurodegenerative conditions, autoimmune disorders, and viral infections. By removing, rather than inhibiting, harmful proteins, this strategy enables direct and sustained therapeutic effects. However, current tools such as PROTACs and molecular glues rely on the ubiquitin-proteasome system (UPS), which introduces key limitations. Their dependency on cellular ubiquitination machinery often results in inconsistent degradation efficiency, limited protein target scope, and vulnerability to resistance mechanisms, such as mutations that interfere with ubiquitination pathways.
This modular technology platform enables targeted degradation of proteins by directly linking them to the proteasome without requiring ubiquitination. The system employs engineered polypeptide adaptors that contain three components: a target-binding domain (e.g., monobodies or nanobodies), a proteasome-binding domain (such as Rad23 UBL or Midnolin), and a flexible linker optimized for proteasomal engagement. These adaptors can be customized with subcellular localization signals for compartment-specific degradation and with affinity domains to target a wide array of intracellular proteins. By directly tethering target proteins to the proteasome, the adaptors eliminate the need for complex enzymatic tagging, resulting in more efficient and predictable protein clearance. This platform enables degradation of targets previously inaccessible by UPS-dependent tools and offers greater control over degradation kinetics and specificity.
Provisional US patent application filed 09/18/2024