Research

The overarching goal of our research program is to use chemistry as a central tool to understand, interrogate, and ultimately control complex life processes. We develop new chemical concepts and molecular systems that enable access and manipulate proteins and pathways that have remained beyond the reach of existing technologies.

Chemical Strategies for Reprogramming Protein Degradation

One direction in our lab focuses on advancing targeted protein degradation (TPD), a chemical biology strategy that uses small molecules to remove disease-driving proteins by redirecting the cell’s protein degradation machinery through E3 ligases. Although TPD has shown substantial promise, its broader application in probing biological systems as well as in therapeutic development has been limited by reliance on a small number of E3 ligases. Our lab aims to address this gap by identifying and validating additional TPD-competent E3 ligases. For example, we identified FBXO22 as a tumor-upregulated E3 ligase that can be exploited to promote degradation of oncoproteins. We further introduced a new concept that cancer-specific E3 ligase mutations can be reprogrammed by small molecules for selective protein degradation, as demonstrated with the recurrent FBXW7-R465C mutation present in tens of thousands of cancer patients. Together, these findings expand the repertoire of TPD-competent E3 ligases and establish new strategies for accessing an expanded degradable proteome.

Chemical Control of Immune Recognition via Cell-Surface Peptides

 A second direction in our lab establishes foundational principles at the interface of chemistry and immunology by demonstrating that peptide antigens displayed on the mammalian cell surface can be directly targeted by small molecules to modulate immune responses. Although the human proteome contains hundreds of thousands of cysteine residues, those presented on the cell surface as part of the immunopeptidome have remained largely unexplored for chemical intervention. Our lab is opening this new area by developing a chemical biology platform to systematically profile cysteine reactivity within the cell-surface immunopeptidome. We discovered that a subset of immunopeptidome cysteines exhibits distinctive chemical reactivity, enabling small-molecule engagement. We further demonstrated that covalent targeting of these residues with rationally designed molecules can trigger immune cell functions, such as phagocytosis. Together, these findings establish a new chemical principle in which covalent small-molecule engagers translate cell-surface peptide antigen reactivity into defined immune outcomes.

Chemical Biology of Hapten-Modified Peptides

A third direction in our lab focuses on hapten-modified peptides that play essential roles in human immunology. These peptides arise when small molecules covalently modify endogenous proteins, generating chemically modified peptide antigens that are subsequently processed and displayed on the cell surface. Once presented, these hapten-modified peptides can drive immune recognition in clinically important contexts such as drug-induced hypersensitivity and allergy. Our lab develops chemo-immunopeptidomics approaches to directly identify and characterize these unique peptide antigens in native systems, thereby uncovering fundamental mechanistic links between chemical reactivity, peptide modification, and immune activation.

Funding Support