Author
Martin, Jacob T.
Other Contributors
Kane, Ravi S.; Tessier, Peter M.; Cramer, Steven M.; Garde, Shekhar; Belfort, Marlene, 1945-;
Date Issued
2014-05
Subject
Chemical and biological engineering
Degree
PhD;
Terms of Use
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.;
Abstract
Here I describe the structure-based design of macromolecular bioconjugates for the effective inhibition of three different diseases with broad public interest: anthrax, influenza, and HIV/AIDS. To that end, I have synthesized multivalent arrangements of bioactive macromolecules (i.e., peptides, proteins, and oligonucleotides) on biocompatible scaffolds in order to enhance the inhibitory efficacy of those biomolecules. Multivalency is the simultaneous interaction of multiple binding elements with multiple target receptors, and this phenomenon underlies a powerful strategy for controlling the potency of bioactive molecules by manipulating their context. For example, some multivalent ligand-receptor interactions are known to exhibit binding avidities that are several orders of magnitude stronger than the corresponding monovalent receptor-ligand binding affinities. An important aspect of this research was the identification of appropriate targets from the etiology of each of these diseases. Once suitable targets were identified, I used strategically-chosen scaffolds to control the multivalent arrangements of targeting ligands. Specifically, the anthrax toxin protective antigen heptamer was the target of multivalent anti-toxin inhibitors that display peptide ligands on either linear or radial scaffolds. Similarly, a conserved region of the influenza hemagglutinin glycoprotein was targeted by a series of linear divalent and polyvalent cell entry inhibitors. Finally, a recently-identified protein ligand for CCR5, a co-receptor for HIV cell attachment and entry, was used for polyvalent display on linear polymer scaffolds, and the ability to obstruct CCR5 binding was shown. The results support the potential for multivalent bioconjugates such as these to lead to very promising therapeutic applications.;
Description
May 2014; School of Engineering
Department
Dept. of Chemical and Biological Engineering;
Publisher
Rensselaer Polytechnic Institute, Troy, NY
Relationships
Rensselaer Theses and Dissertations Online Collection;
Access
Restricted to current Rensselaer faculty, staff and students. Access inquiries may be directed to the Rensselaer Libraries.;