Designing a polyvalent inhibitor of anthrax toxin

Nat Biotechnol. 2001 Oct;19(10):958-61. doi: 10.1038/nbt1001-958.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acrylic Resins
  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / metabolism
  • Animals
  • Antigens, Bacterial*
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / toxicity
  • CHO Cells
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism
  • Cricetinae
  • Drug Design
  • Enzyme-Linked Immunosorbent Assay
  • Peptide Library
  • Peptides / chemical synthesis
  • Peptides / isolation & purification
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Binding
  • Rats
  • Rats, Inbred F344

Substances

  • Acrylic Resins
  • Adenylyl Cyclase Inhibitors
  • Antigens, Bacterial
  • Bacterial Toxins
  • Carrier Proteins
  • Peptide Library
  • Peptides
  • anthrax toxin
  • polyacrylamide
  • Adenylyl Cyclases