title: Use of phage display and polyvalency to design inhibitors of protein-protein interactions.
abstract: We describe the synthesis of an inhibitor that interferes with critical protein-protein interactions occurring during the assembly of anthrax toxin. Using a phage display selection strategy, we isolated a peptide directed against the cell binding moiety of the toxin that was able to interfere with binding of the enzymatic moieties. Because the cell binding moiety of the toxin is a heptamer, the peptide can potentially bind up to seven equivalent sites. We synthesized a polyvalent molecule displaying multiple copies of this peptide and showed that it is a much more potent inhibitor than the free peptide. Because little structural knowledge of the interacting proteins was required to synthesize this inhibitor, we believe that this approach may prove useful in the design of inhibitors of protein-protein interactions in other systems.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mourez
authors.forename: R John
authors.initials: RJ
authors.lastname: Collier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000737:chemistry; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D019151:Peptide Library; D010455:Peptides; C030325:anthrax toxin