Designing a polyvalent inhibitor of anthrax toxin

Screening peptide libraries is a proven strategy for identifying inhibitors of protein-ligand interactions. Compounds identified in these screens ofte n bind to their targets with low affinities. When the target protein is pre sent at a high density on the surface of cells or other biological surfaces , it is sometimes possible to increase the biological activity of a weakly binding ligand by presenting multiple copies of it on the same molecule. We isolated a peptide from a phage display library that binds weakly to the h eptameric cell-binding subunit of anthrax toxin and prevents the interactio n between cell-binding and enzymatic moieties. A molecule consisting of mul tiple copies of this nonnatural peptide, covalently linked to a flexible ba ckbone, prevented assembly of the toxin complex in vitro and blocked toxin action in an animal model. This result demonstrates that protein-protein in teractions can be inhibited by a synthetic, polymeric, polyvalent inhibitor in vivo.