Modern DNA sequencing and editing technologies have revolutionized our understanding of the genetic and molecular basis of human disease. However, many disease-relevant genes encode proteins that are poorly characterized and/or are considered pharmacologically inaccessible, which has hindered our understanding of disease mechanisms and translating this knowledge into new therapies. Chemical probes offer a valuable way to directly interrogate the function and disease-relevance of proteins and they can also serve as valuable leads for new therapies, yet most proteins in the human proteome lack small-molecule tools to study their function. The Parker lab aims to develop various chemical tools and integrate them with powerful proteomic methods, to interrogate the function and contributions of proteins that have pathophysiological roles in human disease but currently lack useful chemical probes.
Chemical biology approaches to study molecular transport
Low molecular weight molecules (e.g. amino acids, glycans, lipids, ions, nucleotides, etc) play essential roles in cellular signaling, metabolism and communication. Disease is often associated with the dysregulation of these molecules, thus new strategies to study and control their regulation could prove valuable for therapeutic intervention. Transporters can be considered molecular gates of the cell, allowing these molecules to traverse through cellular barriers (i.e. membranes), thus serving as crucial points of control for various processes. However, despite their critical functions and therapeutic promise, many transporters, such as the solute carrier (SLC) super family, remain largely underexplored. Using powerful chemical proteomic platforms from our lab, we are developing chemical probes to explore SLC-mediated transport and function in the context of basic cellular biology and disease pathways .
The transition of cells from one state to another state, for example, the acquisition of oncogenic mutations or cellular activation (e.g. activation of T-cells), is associated with alterations of protein expression, protein location, protein- and metabolite-interactions (PPIs and PMIs), and post-translational modifications (PTMs). These changes can affect protein structure and function, as well as accessibility by small molecules. We are developing chemoproteomic strategies to create global "fingerprints" of these alterations, particularly those resultant from non-expression based changes, and furthermore, to deconvolute consequences on protein pharmacological tractability.
Illuminating protein-metabolite interactions
Small molecule metabolites can interact with proteins to modulate their function, however, it remains a challenge to identify these interactions, specifically in endogenous settings. Our lab is creating chemical probes and combining them with mass spectrometry to catalog various metabolite-protein interactions as well as examine their influence on protein function and cellular physiology.