Human genetics has underscored the central role that the immune system plays as both a causal basis for and guardian against diseases ranging from autoimmune and immunodeficiency disorders to neurodegeneration and cancer. However, despite significant advances in our understanding of the human immune system, chemical probes are still lacking for many immunologically relevant proteins, which severely limits our ability to control immune system function for the benefit of basic research and human health. Research in our group focuses on the development of new chemistries and chemical proteomic approaches to address these limitations.
State-dependent cysteine reactivity
Methods for exerting control over relative quantities and activation states of different immune cell populations could have profound implications for clinical outcomes in autoimmunity, cancer, and infection. Previous studies have underscored the role of transcriptional changes in immune cell development, however the extent to which these and other state-dependent changes in biochemistry create a landscape of new opportunities for targeting and selectively manipulating these immune states with small molecules remains largely underexplored. Furthermore, the post-translational drivers of these changes are also frequently poorly understood. To address these shortcomings, we will develop and apply advanced chemical proteomic platforms to interrogate the state-dependent changes in the reactive proteome. This approach will serve as a unified platform to achieve our long-term goal of creating advanced chemical probes to study and control the human immune and nervous systems in a state-dependent manner for basic and translational research purposes.
Covalent small-molecule protein degraders
Conventional approaches to drug development involve the use of non-covalent or covalent small molecules, which target specific regions in the proteins of interest. While generally successful, this approach encounters limitations with multidomain proteins, where inhibition of one of the domains is not sufficient for the desired phenotype. In order to overcome these limitations, small molecules have been developed that have the capability of targeting new sites in proteins of interest or degrading the protein as a whole. We have recently identified cysteine-reactive electrophiles as privileged scaffolds affecting protein stability and expression levels. We will leverage our knowledge on the special capacity of cysteine-reactive small-molecule electrophiles to affect protein stability and perturb immune system function, and will aim to develop global mass spectrometry (MS)-enabled approaches for identification of covalent, small-molecule electrophile protein degraders. The findings resulting from these efforts will (1) deepen our understanding of the pharmacology of protein stability, identifying proteins or protein complexes susceptible to small molecule-induced degradation, and (2) provide advanced chemical probes for studying the corresponding biology regulated by these protein targets.
Development of new chemical probes for immune-relevant proteins
While more traditional drug development approaches focus on the development of active site inhibitors of enzymes like kinases, there is a growing appreciation of the importance of scaffolding function for these proteins to control signal transduction in immune signaling pathways. We have recently used an integrated chemical proteomic and phenotypic screening approach to generate a global and site-specific portrait of small molecule electrophile-protein interactions in primary immune cells and further identify “tractable” targets for electrophilic chemical probe development, including sites at protein-protein interaction (PPI) surfaces of immune-relevant adaptors, E3 ligases, proteases, and transcription factors. We aim to (1) functionally characterize the newly discovered cysteine liganding sites at PPI interfaces of key immune-relevant proteins, including the importance of liganding events for the disruption of the known protein-protein interactions; (2) use a chemical proteomic-guided approach for the development of more potent and selective chemical probes; and (3) apply our advanced chemical tools to study the relevance of the disruption of the scaffolding functions of immune-relevant proteins to the downstream signaling pathways and inflammation. Efforts in the group are also aimed at the development of novel chemical scaffolds targeting cysteine and other nucleophilic amino acid residues.