Design of monodisperse and well-defined polypeptide-based polyvalent inhibitors of anthrax toxin.
The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure-activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells.
Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180 (USA).
Sanket
S
Patke
Mohan
M
Boggara
Ronak
R
Maheshwari
Sunit K
SK
Srivastava
Manish
M
Arha
Marc
M
Douaisi
Jacob T
JT
Martin
Ian B
IB
Harvey
Matthew
M
Brier
Tania
T
Rosen
Jeremy
J
Mogridge
Ravi S
RS
Kane
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry*; D013816:Thermodynamics
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010455:Peptides; C030325:anthrax toxin
anthrax toxin; multivalency; periodic polypeptides; protein engineering; structure-activity relationships