(338a) Young Investigator Award Lecture - the Design of Nanoscale Polyvalent Therapeutics

This talk will describe our efforts to interface biomolecules with nanomaterials and nanoscale scaffolds for designing potent therapeutics.

We are designing potent inhibitors of anthrax toxin based on the concept of polyvalency ? the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another. Since the major symptoms and death from anthrax are due primarily to the action of anthrax toxin, the toxin is a prime target for therapeutic intervention. We will describe the design and characterization of polyvalent inhibitors that are several orders of magnitude more potent than the corresponding monovalent inhibitors and can neutralize anthrax toxin in vivo. Studies relating the composition and structure of these inhibitors to their activity have shed light on fundamental aspects of polyvalent recognition, including the role of ?statistical pattern matching?. We will also discuss the structure-based design of potent oligovalent toxin inhibitors.

Next, we will describe the design of polyvalent inhibitors that target the cellular receptors for anthrax toxin. We used phage display to identify novel peptides that bind to the two cellular receptors for anthrax toxin, and NMR spectroscopy to characterize the peptide-protein interactions; the corresponding polyvalent inhibitors neutralize anthrax toxin both in vitro and in vivo. Receptor-directed therapeutics are particularly promising, because they may help counter the emerging problem of pathogen resistance to antimicrobial therapeutics. We will discuss applications of this concept for the inhibition of other important targets, such as HIV. Finally, we will discuss the ability to remotely control the activity of proteins adsorbed onto carbon nanotubes. We will discuss the mechanistic basis of this phenomenon, and its use to design polyvalent nanotube conjugates that selectively destroy anthrax toxin from a mixture of proteins.