1. Polyvalency: The Design of Nanoscale Polyvalent Therapeutics
We have considerable expertise in the application of polyvalency – the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another. In previous work, we have used polyvalency to enhance the potency of toxin inhibitors by orders of magnitude and have designed nanoscale polyvalent inhibitors that are active in vivo. We have also made important contributions to a fundamental understanding of polyvalent recognition. We are currently exploring the use of this approach to combat AIDS, Influenza, and protein misfolding diseases (e.g., Alzheimer’s disease).
2. Vaccines: The Design of Nanoscale Scaffolds for Controlling Antigen Presentation
The group is also designing approaches to control antigen presentation from nanoscale scaffolds as part of novel strategies for designing vaccines. One current area of interest involves the development of “universal” influenza vaccines. Seasonal flu vaccines typically induce an immune response against the globular head of hemagglutinin – the major antigenic protein in the viral envelope. However, given the high variability of the head domain, the antibodies directed against this region are narrow in their specificity, requiring annual vaccination. In contrast, antibodies that target the highly conserved stalk domain of hemagglutinin are able to neutralize multiple viral subtypes. We are developing approaches to control antigen presentation in order to elicit these broadly protective antibodies that might provide universal influenza virus protection. We are also exploring approaches to design more effective vaccines that target several other important pathogens including respiratory syncytial virus and malaria parasites.
3. Stem Cells: Controlling Stem Cell Fate Using Optogenetics and Polyvalency
We have helped develop optogenetic methods – techniques for controlling cellular function using light. These methods enable a light input to be channeled into defined signaling pathways by the nanoscale assembly of biomolecules inside target cells. We are using optogenetic methods to illuminate basic signaling mechanisms in stem cells (e.g., Wnt/b-catenin). We are interested in developing new optogenetic tools for controlling stem cell function. We are also designing complementary approaches that use polyvalent ligands to control stem cell fate. Cellular signaling is often activated by the clustering of cellular receptors. The design of synthetic polyvalent ligands is a promising approach to modulate clustering of stem cell receptors and to elucidate fundamental mechanisms in cellular signaling. Such molecules could serve as both powerful biological tools and as potent therapeutics. We are designing polyvalent ligands that target several different signaling pathways in stem cells.
4. Antimicrobials: The Design of Enzymes and Enzyme-Containing Nanocomposites
One of the major goals of our research in this area has been to develop a fundamental understanding of the molecular level interactions that govern the structure, activity, and stability of proteins on the surface of nanoscale materials. We have investigated the structure and function of enzymes attached to a variety of nanomaterials. We have also incorporated enzyme-nanotube conjugates into nanocomposite coatings that target antibiotic-resistant pathogens such as MRSA (methicillin-resistant S. aureus). We recently reported an approach to identify putative lytic enzymes – enzymes that lyse target bacteria. Using in silico techniques, we identified and characterized an enzyme with lytic activity against bacilli. We are currently using a similar approach to identify new lytic enzymes that target other important pathogens such as S. aureus and C. difficile.