"The Design of Nanoscale Therapeutics and Nanostructured Materials"

The design of polyvalent molecules presenting multiple copies of a specific ligand represents a promising strategy to inhibit pathogens and bacterial toxins. We will first describe the design of polyvalent inhibitors that are orders of magnitude more active than the corresponding monovalent molecules and can neutralize anthrax toxin in vivo. We recently described a thermodynamic analysis to help clarify the theoretical basis for the large enhancements in avidity due to polyvalency. We have used this understanding to guide the structure-based design of potent synthetic polyvalent ligands. The ability to control independently the valency and the spacing between ligands is particularly valuable for these design efforts. To that end, we recently designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. Studies relating the composition and structure of polyvalent inhibitors to their activity have also shed light on fundamental aspects of polyvalent recognition, including the role of “pattern matching”. We will also discuss other applications of polyvalent molecules ranging from the inhibition of pathogens (e.g., the influenza virus) to controlling the nanoscale organization of cellular receptors to regulate signaling and stem cell fate.
    In addition to the inhibition of bacterial toxins, we are also investigating approaches to target pathogenic bacteria. In particular, the emergence of antimicrobial resistance has been a growing concern. We have been exploring an enzyme-based approach to combat pathogenic bacteria. We will describe an approach that we have developed to identify novel bacteriolytic enzymes targeting a variety of bacterial pathogens. We have also investigated the structure and function of these and other enzymes when immobilized onto nanomaterials such as carbon nanotubes. Our studies indicate that the nanoscale environment can significantly influence the activity and stability of these proteins. We have used the highly stable and active nanomaterial-protein conjugates to form nanocomposite films that are effective against antibiotic-resistant bacteria including methicillin-resistant S. aureus (MRSA).