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The Yu lab at GSU is dedicated to developing innovative chemical tools to study signal transduction and medicine in the context of protein-biomolecule interactions. Proteins interact with proteins, carbohydrates, nucleic acids, and lipids. These interactions govern every aspect of life. Deciphering these interactions can contribute to the understanding of the fundamental aspects of life and open up diverse opportunities for therapeutic intervention.


Despite the critical roles of protein-biomolecule interactions, the lack of enabling tools greatly hindered the efforts to study such interactions and leverage these interactions for therapeutic purposes. The current methods of capturing protein-biomolecule interactions such as affinity purification-mass spectrometry relies on the reversible interaction, which often leads to large variation, false positive signals, and cannot distinguish direct from indirect interactors. To address these challenges, our lab will leverage our expertise in organic synthesis, molecular biology, and protein science to covalently capture these interactions for mechanistic studies and therapeutic developments.


1. Mapping protein-biomolecule interactions via protein engineering

This strategy genetically incorporates a latent bioreactive unnatural amino acid (Uaa), into a protein of interest. The latent Uaa itself has low activity, avoiding non-specific interactions. However, upon protein-target binding, the close contact would trigger the cross-linking reaction between the latent Uaa and the nucleophiles on the target. These proximity-enabled chemical reactions can irreversibly cross-linking the interacting protein-biomolecule. Subsequent mass spectrometry analysis would reveal the interacting biomolecules in high specificity. The proximity-enabled chemistry used in our lab includes sulfur(VI) fluoride exchange (SuFEx) and phosphorus fluoride exchange (PFEx). Additionally, we use photo-activated cross-linkers such as aryl azides and diazirines as complementary strategies for the proximity-enabled chemical cross-linkers.


Currently, we are focusing on probing protein post-translational modification (PTM)-mediated protein-protein interactions (PPIs) and identify new PPIs as therapeutic targets.


2. Probing protein-biomolecule interactions via covalent small molecule probes

Besides protein engineering, we are developing covalent small molecule probes to study signal transduction and facilitate drug discovery. Harvesting the power of organic synthesis and medicinal chemistry, we can install versatile chemical functional groups into small molecules of interest and investigate the targets and biological significance of such molecules.


3. Small molecule drug discovery targeting challenging targets

There is a growing number of disease-related targets that have been discovered but deemed “undruggable.” These targets typically have flat surfaces without well-defined grooves or pockets for binding, making therapeutic development challenging. To address these challenges, we collaborate closely with structural biologists and employ a combination of innovative approaches, including novel assay development, AI-powered protein-ligand interaction simulations, and high-throughput screening.


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