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 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.
Mourez
M
M
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Kane
R S
RS
Mogridge
J
J
Metallo
S
S
Deschatelets
P
P
Sellman
B R
BR
Whitesides
G M
GM
Collier
R J
RJ
D000180:Acrylic Resins; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D000099166:Polyacrylamides
D000180:Acrylic Resins; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002352:Carrier Proteins; D019151:Peptide Library; D010455:Peptides; D000099166:Polyacrylamides; C030325:anthrax toxin