Designing a polyvalent inhibitor of anthrax toxin

• Published in: Nature biotechnology 2001-10, Vol.19 (10), p.958-961
• Main Authors: Mourez, Michael, Kane, Ravi S., Mogridge, Jeremy, Metallo, Steve, Deschatelets, Pascal, Sellman, Bret R., Whitesides, George M., Collier, R. John
• Format: Article
• Language: English
• Subjects: Acrylic Resins; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases - metabolism; Agriculture; Animal models; Animals; Anthrax; anthrax toxin; Antigens, Bacterial; Bacillus anthracis; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - metabolism; Bacterial Toxins - toxicity; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; CHO Cells; Cricetinae; Drug Design; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Libraries; Life Sciences; Ligands; Other active biomolecules; Peptide Library; Peptides; Peptides - chemical synthesis; Peptides - isolation & purification; Peptides - metabolism; Peptides - pharmacology; Production of active biomolecules; Protein Binding; Proteins; Publishing; Rats; Rats, Inbred F344; Toxins
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1001-958

Screening peptide libraries is a proven strategy for identifying inhibitors of protein–ligand interactions. Compounds identified in these screens often bind to their targets with low affinities. When the target protein is present 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 heptameric cell-binding subunit of anthrax toxin and prevents the interaction between cell-binding and enzymatic moieties. A molecule consisting of multiple copies of this nonnatural peptide, covalently linked to a flexible backbone, prevented assembly of the toxin complex in vitro and blocked toxin action in an animal model. This result demonstrates that protein–protein interactions can be inhibited by a synthetic, polymeric, polyvalent inhibitor in vivo .