Oligomeric proteins : toxicity, aggregation, and polyvalent inhibition
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Authors
Patke, Sanket
Issue Date
2013-12
Type
Electronic thesis
Thesis
Thesis
Language
ENG
Keywords
Chemical and biological engineering
Alternative Title
Abstract
Finally, we designed polyvalent molecules that bind with high affinity to protein oligomers. Specifically, we used a structure-based design strategy to engineer monodisperse and well-defined polyvalent inhibitors of anthrax lethal toxin using polypeptide scaffolds. Specifically, we expressed and purified polypeptides incorporating multiple copies of an inhibitory [PA63]7 -binding peptide separated by peptide linkers. A characteristic feature of this design was the ability to control precisely and independently the valency and the spacing between ligands. We used computational studies to guide our choice of linker lengths and tested the validity of the design using cell viability studies. We found that the resulting polypeptides were five orders of magnitude more potent than monovalent ligands in inhibiting anthrax lethal toxin in vitro. We have therefore demonstrated a simple strategy to rationally design monodisperse polyvalent molecules that could be broadly applicable for the inhibition of toxins and pathogens.
Description
December 2013
School of Engineering
School of Engineering
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY