Research in the Moellering Lab lies at the interface of chemistry and biology, with an eye towards understanding and intervening in human disease. By integrating chemical synthesis, cell biology and mass spectrometry platforms, our research aims to identify novel biological mechanisms underlying diseases, such as diabetes and cancer, and to subsequently develop innovative diagnostic and therapeutic modalities to impact these disorders. We are specifically interested in developing new chemical tools and technologies to study complexity and dynamics in the proteome, thus enabling targeted manipulation of protein targets and the pathways they govern. We are actively pursuing projects in the following research areas:
Metabolic signaling and protein post-translational modifications in disease:
Control of protein structure and function via reversible small molecule binding and covalent post-translational modifications are well-established and conserved biochemical regulatory mechanisms in cell biology. These events integrate diverse signaling pathways in the cell and also allow for significant expansion of the chemical and functional diversity afforded by finite genetic products (~23,000) by more than an order of magnitude (~1,000,000 unique proteins). While these mechanisms are involved in all aspects of biology, we lack a complete map of these chemical modifications, including their tissue-, cell- and temporal regulation and, importantly, their regulatory roles in normal and pathologic cell signaling. Our group has several areas of active research into the origins and roles of novel protein modification networks in the regulation of metabolic homeostasis, particularly within the contexts of aging, metabolic disease and cancer. For example, we have discovered several novel protein post-translational modifications resulting from the interactions between proteins and reactive primary metabolites formed by glucose, a ubiquitous energy source in life. These non-enzymatic modifications represent a direct connection between glycolytic flux and alterations in the structure and function of key proteins, including glycolytic enzymes themselves, pointing to the existence of an ancient and likely biomedically important intrinsic feedback pathway in mammalian cells. Using a combination of cell biology, mass spectrometry and chemical probe development, we are exploring the fundamental biochemical processes that regulate the formation and removal of these modifications, their effects on target protein structure and function, and their ability to serve as a novel form of intracellular signaling, integrating glucose metabolism with other pathways in normal as well as diseased processes.
Harnessing chemical proteomic technologies for discovery biology and chemical probe development:
Our group is developing novel chemical proteomic technology platforms with applications ranging from basic biology to drug discovery. One area of active research is the development of proteomic platforms for the discovery and mapping of protein-ligand (e.g. protein-metabolite, protein-drug, protein-protein) interaction networks in native cellular environments. Connecting ligands to their biologically relevant binding partner(s) is a major challenge in unraveling cellular signaling events as well as understanding the mechanism of action for chemical probes and even existing drugs. We are developing chemical proteomic platforms that will enable systems-level views of ligand interactions proteome-wide. Specific interest areas included: development of label-free chemical proteomic platforms; development of novel chemical probes for poorly characterized protein families; application of proteomic platforms in relevant disease models to discover new diagnostic and/or therapeutic targets in cancer.
Synthetic protein and peptide therapeutics:
Nature employs a myriad of chemical modifications to control protein structure and function. For example, subtle chemical transformations like disulfide bridge formation and protein acetylation can have profound effects on protein structure, stability and half-life. In addition to our exploration of natural protein modification networks in cellular biochemistry and physiology, our group is interested in drawing upon these strategies to develop synthetically-modified protein- and peptide-based chemical probes. These efforts compliment our interests in disease associated biological pathways by enabling chemical probe development for classes of biomolecules that have proven difficult to target with conventional small molecules. Protein-based drugs have become a major area of drug discovery in the past few decades, mainly owing to their ability to bind protein targets with exceptional potency and specificity relative to traditional small molecule drugs. These desirable properties, however, are often accompanied by limitations in target space, route of administration and stability. Our group is developing novel approaches to synthetically modify or mimic proteins and peptides to improve their drug-like properties, which include protease-resistance, in vivo half-life, and the ability to access intracellular targets. Through total- and semi-synthesis, we are employing these strategies to develop novel classes of peptide and protein mimetics to address difficult biological targets in human diseases such as diabetes and cancer.
