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Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin
Author(s) -
Patke Sanket,
Boggara Mohan,
Maheshwari Ronak,
Srivastava Sunit K.,
Arha Manish,
Douaisi Marc,
Martin Jacob T.,
Harvey Ian B.,
Brier Matthew,
Rosen Tania,
Mogridge Jeremy,
Kane Ravi S.
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201400870
Subject(s) - anthrax toxin , valency , rational design , chemistry , peptide , linker , small molecule , dendrimer , ligand (biochemistry) , receptor , biochemistry , combinatorial chemistry , nanotechnology , materials science , fusion protein , linguistics , philosophy , computer science , gene , recombinant dna , operating system
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.