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 an...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2014-07, Vol.53 (31), p.8037-8040
Main Authors: 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.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Anthrax
anthrax toxin
Antigens, Bacterial
Bacterial Toxins - antagonists & inhibitors
Design
Inhibitors
Ligands
Medical research
multivalency
Nanostructure
Pathogens
Peptides
Peptides - chemistry
periodic polypeptides
Polypeptides
protein engineering
Reproduction
Strategy
structure-activity relationships
Thermodynamics
Toxins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Quantity and spacing: A protein‐engineering approach was designed to develop monodisperse polyvalent molecules based on tandem‐repeat polypeptide scaffolds. This approach allowed for precise control over ligand spacing and valency of the polyvalent molecules. This approach was applied to develop potent inhibitors of anthrax lethal toxin.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201400870