Research & Projects
Research at the Muno Lab interfaces between chemistry and cell biology. Specifically, the lab develops chemistry-based tools to study and regulate biological systems. These tools include bioorthogonal chemical reporters, bespoke glycans and glycan ligands, redox-active biomaterials, and deep eutectic solvents. The overarching goal is to use these tools to study and regulate posttranslational modifications and cell fate that affect human health. Our research focuses on four distinct areas, including the design and synthesis of the following:
bioorthogonal chemical reporters to study posttranslational modifications,
glycomimetic and glycan ligands to regulate cell-cell interactions,
redox-active biomaterials to regulate radicals, and
deep eutectic solvents for cytosolic delivery of biologics.
Design of Bioorthogonal Chemical Reporters
Bioorthogonal chemistry is a well-established and reliable technology to study posttranslational modifications, but several drawbacks limit its scope of application. Foremost among these drawbacks is the inefficient incorporation of the state-of-the-art azide-based chemical reporter into biomolecules due to steric constraints. Therefore, steric-free bioorthogonal chemistry reporters are emerging as an alternative to the azide-based reporter. We are developing fluorine-based steric-free bioorthogonal chemical reporters to study protein acylation, including protein lactylation. We investigate these steric-free reporters in live cell imaging of acylation dynamics or proteomic analysis to distinguish cell type.
Figure 1: Chemical reporters can label cellular proteins for detection
Design of glycomimetic and glycan ligands to regulate cell-cell interaction
Glycans are pivotal to cell development, with aberrant glycosylation defining many dysfunctional cellular processes. Nevertheless, targeting glycans to restore dysfunctional processes remains an underexploited therapeutic modality. The modification of glycan structure by use of glycomimetic or glycan ligands offers an approach to alter the biological function of glycans. We are developing mimics and ligands of sialic acid, a cell-surface glycan with implications for cell-cell interaction. The goal is to design mimics and ligands that regulate the interaction of 1) natural killer cells with cancer cells, 2) viruses with host cells, and 3) leukocytes with endothelial cells.
Figure 2: Glycomimetic or glycan ligands can regulate immune cell-cancer cell interaction
Design of redox-active biomaterial to regulate free radical generation
Radicals are as crucial in cell biology as they are in chemical processes. Generated by normal physiological processes, radicals play critical roles in cell signaling processes, contributing to host defence against invading pathogens or damaging cells to drive the development of several diseases. Their importance to life necessitates the evolution of mechanisms to regulate their concentration and, therefore, their effect on the optimal functioning of cells. However, with aging, these mechanisms become dysfunctional, leading, in most cases, to the body’s inability to regulate the biological effects of radicals. We are developing: 1) redox-active biomaterials that generate radicals, killing invading pathogens or malignant cells, and 2) redox-active biomaterials that quench radicals, protecting cells and mitigating the effect of radicals on disease development.
Figure 3: Treatment of methicillin-resistant Staphylococcus aureus with redox-active dendrimer induced oxidative stress, killing the bacteria (red arrow)
Design of bioderived deep eutectic solvents to transport biologics to the cytosol
Biologics, including peptides, proteins, and nucleic acids, are increasingly being investigated as a therapy for several diseases. Most biologics must interact with their intracellular targets to elicit a therapeutic response. A challenge, however, is that their large size limits transport across the cell membrane. Instead, biologics rely on endocytosis for cell uptake, a process that traps them within endocytic vesicles, separating them from their targets. Therefore, bypassing endosomal entrapment is critical therapeutic efficacy of biologics but remains challenging in biologic delivery. The Muno Research Lab is developing biocompatible deep eutectic solvents that directly transport biologics across the cell membrane, bypassing endosomal transport. We are also addressing fundamental questions on how deep eutectic solvents enable cytosolic transport to guide the development of new delivery materials.
Figure 4: Deep eutectic solvent enabled cytosolic delivery of m-Cherry protein to mesenchymal stem cells. (a) Control (b) deep eutectic solvent treated.