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Designing a polyvalent inhibitor of anthrax toxin

Nature Biotechnology volume 19, pages 958–961 (2001)Cite this article

Abstract

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.

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Figure 1: Assembly of anthrax toxin complexes and their entry into cells.
Figure 2: Selection of bacteriophages binding to PA63 heptamer at or near the EF/LF site.
Figure 3: Inhibition of toxin action in cell culture.

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Acknowledgements

This work was supported by grants to R.J.C., G.M.W., and B.R.S. from the National Institutes of Health (NIH), and to G.M.W. from the Defense Advanced Research Projects Agency (DARPA; Arlington, VA). M.M. received a fellowship from the French Defense Advanced Research Projects Agency (DSP/DGA) and the Philippe Fondation. J.M. was supported in part by a Medical Research Council of Canada postdoctoral fellowship. P.D. is a Fonds pour la Formation de Chercheurs et l'Aide à la Recherche (FCAR; Québec, PQ) research fellow. R.J.C. has financial interest in AVANT Immunotherapeutics, Inc.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, MA

    Michael Mourez, Jeremy Mogridge, Bret R. Sellman & R. John Collier

  2. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, 02138, MA

    Ravi S. Kane, Steve Metallo, Pascal Deschatelets & George M. Whitesides

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  1. Michael Mourez
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  2. Ravi S. Kane
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Correspondence to R. John Collier.

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Mourez, M., Kane, R., Mogridge, J. et al. Designing a polyvalent inhibitor of anthrax toxin. Nat Biotechnol 19, 958–961 (2001). https://doi.org/10.1038/nbt1001-958

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