Despite enormous efforts to advance traditional pharmacology approaches, more than three quarters of all human proteins remain beyond the reach of therapeutic development. Targeted protein degradation (TPD) is a novel approach that could overcome this and other limitations, and thus represents a promising therapeutic strategy. TPD is based on small molecules, generally called 'degraders,' which can eliminate disease-causing proteins by causing their destabilization. Mechanistically, these degrader drugs repurpose the cellular protein quality control system, tweaking it to recognize and eliminate harmful proteins. In detail, they re-direct members of the protein family of E3 ubiquitin ligases (E3s) towards the disease-causing target protein. This leads to a "molecular earmarking" of the harmful protein via a process called 'ubiquitination.' Subsequently, the ubiquitinated protein is recognized and degraded by the molecular machine called the proteasome, which serves as the cellular garbage disposal system.
Drug discovery: First rational strategy to find molecular glue degraders
- PhysOrg
- 3. 8 2020 (18:29)