Development of collagen peptide-based biomaterials and synthesis of small molecules targeted against anthrax protective antigen
Abstract
Tissue Engineering (TE) is the interdisciplinary field that focuses on developing strategies for creating functional and healthy tissue for the replacement and regeneration of damaged organs and tissue. One strategy in this area is to use hydrogels as temporary scaffolds for cell growth and differentiation using biomimetic materials such as collagen peptides. Collagen is one of the most abundant proteins found in the connective tissue of mammals providing physical support for cell growth. A key feature of collagen is the ability of single peptide strands to acquire a triple helical conformation, critical for the subsequent self-assembly into high order fibers and fibrous networks in nature. Therefore, in this study a hydrogel system was designed by conjugating collagen peptides to an 8-arm polyethylene glycol star polymer to yield hydrogels via the physical cross-linking of the collagen triple helices. Various physical characterization studies proved that this collagen peptide-based hydrogel possessed desirable viscoelastic and biocompatible properties to function as a 3D matrix with the potential to induce differentiation of the mesenchymal stem cells (MSCs). It was also found that the hydrogel had a thermoresponsive feature that could be tuned when altering the collagen peptide sequence. Also in this work, another collagen-based materials were designed to self-assemble into supramolecular structure via aromatic interactions. For this purpose, we attached various aromatic molecules in the middle of the peptide sequence in a radial-mediated design that yielded various structures such as hollow spheres and insoluble fibers. In the last part of this work, the synthesis of small peptidomimetic molecules targeted against anthrax protective antigen will be discussed. Protective antigen plays an important role during anthrax infection by oligomerizing into a pore structure that translocates other anthrax toxins inside of the cells. For this reason, various small molecules were designed by the CAVEAT computer software to target the oligomerization process, synthesized and evaluated in a biological assay. One of the molecules was able to modestly rescue a macrophage cell line from anthrax toxin-induced cell death, and is one of the few examples of small molecules targeted against the pore formation of protective antigen.
Degree
Ph.D.
Advisors
Chmielewski, Purdue University.
Subject Area
Chemistry|Biochemistry
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