Protein-Protein Interactions (PPIs) are fundamental to many important cellular functions and the ability to disrupt or stabilize PPIs offers novel targets for new therapeutics. Despite the huge potential in targeting the interfaces between proteins, discovering small-molecule drugs that disrupt PPIs is an enormous challenge. Therefore, I am very interested in investigating biological systems and pathways with specific protein-protein interactions to reveal potential targets and develop strategies to screen for small-molecule drugs. I am involved in the study of two major classes of proteins – tumor necrosis factor receptors (TNFRs) and intrinsically disordered proteins (IDPs).
Research focus (TNFRs)
Tumor necrosis factor receptor 1 (TNFR1) is a member of the TNFR superfamily which can be activated by binding to its cognate ligand, TNF-α, via its extracellular domain. Ligand binding leads to network formation and signaling cascade culminating with NF-ĸB activation and inflammatory response, resulting in inflammatory and autoimmune diseases such as rheumatoid arthritis. Therapeutic targeting of TNFR1 is a billion-dollar industry. Current clinically active therapeutics (e.g. etanercept and infliximab) act through sequestration of ligand, which induces dangerous side effects due to off-target inhibition of related TNFRs. Thus, alternate strategies that target receptor-receptor interactions are desperately being pursued. This motivates the discovery of small-molecule drugs that directly target TNFR1 to disrupt the receptor-receptor interactions and inhibit downstream signaling.
We have engineered a stable cell biosensor, expressing fluorophore-tagged TNFR1 and exhibiting fluorescence resonance energy transfer (FRET), to study receptor-receptor interactions through time-resolved FRET, with an emphasis on interpreting receptor function in terms of their structural dynamics. Pilot screening of small-molecule library with TNFR1 FRET biosensor has successfully identified small-molecule inhibitors of TNFR1 signaling and future work includes moving on to large screening and establishing structure-activity relationship of lead compounds. Our biosensor provides a very promising platform for high-throughput screening of small molecules as potential therapeutics for inflammatory and autoimmune diseases. Such a strategy should be generally applicable to other members of the TNFR superfamily, as well as to oligomeric receptors in general.