AI-Guided Design of Synthetic Proteins for Targeted Protein Degradation

Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy for eliminating disease-causing proteins that are difficult to inhibit using conventional small-molecule drugs. Technologies such as PROTACs and LYTACs have demonstrated the potential of harnessing the cell’s ubiquitin–proteasome and lysosomal systems to selectively degrade specific proteins. However, many proteins remain “undruggable” due to the lack of suitable binding ligands. Advances in artificial intelligence and protein engineering offer new opportunities to design synthetic proteins capable of selectively recognizing and degrading these challenging targets.

This PhD project will draw on expertise in the A. Wood and D’Angiolella laboratories on targeted protein degradation and ubiquitin biology, with co-supervision by Dr Chris Wood: an expert in synthetic protein design based in the School of Biology and Engineering. Recent breakthroughs in computational protein modeling, including systems such as AlphaFold and generative protein design approaches like ProteinMPNN and RFdiffusion, enable the rational design of novel protein binders with high specificity and stability. These tools are used routinely in the C. Wood group, and will be leveraged to generate bifunctional proteins that degrade targets via recruitment to E3 ligases or lysosomes. To maximise the impact of this technology platform locally, target proteins will be prioritised based on disease-areas-of-interest to other researchers in the IGC and elsewhere in Edinburgh; specifically, cholangiocarcinoma (collaboration, Boulter), colorectal cancer (collaboration, Myant) and glioblastoma (collaboration, Pollard), facilitating target validation in cutting edge disease models.

By integrating machine learning with synthetic biology and structural bioinformatics, this project seeks to expand the toolbox for targeted protein degradation beyond small molecules. The resulting AI-driven design framework could accelerate the development of next-generation biologic degraders and open new avenues for therapeutic intervention against currently intractable disease targets. It will bridge several research themes at the IGC while also equiping the student with a highly relevant skillset to pursue a career in academia or industry.