Browsing by Subject "Depsipeptides"
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Item The development of depsipeptides as tissue engineering scaffolds : synthesis, characterization, and self-assembly into hydrogels(2013-05) Nguyen, Mary Minh Chau; Suggs, Laura J.The development of novel, peptide based structures for tissue engineering materials has been widely researched, and its popularity can be attributed to advancements in technological analysis methods. Using principles based on protein structure and organization, this work describes the novel self-assembly of depsipeptides, which incorporate alternating esters within a native peptide backbone. Chapter 1 introduces and reviews peptide mimics for their utility for tissue engineering applications. Chapter 2 describes the methodology in synthesizing and characterization a depsipeptide library using both solution and solid phase methods. Chapter 3 discusses the effects of depsipeptide length, concentration, and sequence within a range of ionic concentrations and pH ranges on the self-assembly of depsipeptides into spherical nanostructures, fibers, or hydrogels. Chapter 4 describes proposed methods to increase the rate of gelation, followed by discussions of biocompatibility studies from other self-assembling peptide and modified-peptide systems in vitro and in vivo. The work described in this dissertation demonstrates that the synthesis and self-assembly of a depsipeptide family which alternates esters into a native peptide backbone does not disrupt the formation of higher order structures. This study illustrates the potential to synthesize a wide range of depsipeptides with variable side chains and hydrophobic character, as understanding these effects on self-assembly is imperative to the development of biomimetic materials for tissue engineering applications.Item Probing the effects of backbone ester substitution on self-assembly and biological activity of short depsipeptides(2015-05) Eckes, Kevin Michael; Suggs, Laura J.; Iverson, Brent; Ren, Pengyu; Shear, Jason; Stachowiak, JeanneHydrogel materials composed of self-assembled amphiphilic peptides show great promise for use as injectable, highly biocompatible biomaterials for tissue regeneration applications. However, peptides do not easily degrade naturally without the presence of proteolytic enzymes, which recognize specific peptide sequences and are specific to certain cell and tissue types. In this dissertation, we evaluate the self-assembly and bioactivity of backbone ester-containing depsipeptides that are degradable by alkaline or acid hydrolysis as the basis for hydrogel materials, in order to circumvent any inflammation and immunogenicity caused by peptide materials that persist in the body. The self-assembly of depsipeptides has not been widely explored, thus we first studied the self-assembly of a simple N-protected dipeptide and its depsipeptide analogue both experimentally and computationally to evaluate the relative importance of hydrogen-bonding interactions mediated by the single amide bond in driving and stabilizing self-assembly. We determined that amide-amide hydrogen bonding interactions are not strictly necessary for self-assembly. We next hypothesized that amide-mediated hydrogen bonding may not be necessary for mediating peptide-protein interactions. To test this hypothesis in a simple, well-characterized system, we synthesized a depsipeptide analogue of a peptide containing the Arg-Asp-Gly (RGD) sequence, which is found in extracellular matrix proteins and known to promote cell adhesion through binding of cell surface integrin proteins. As before, the RGD analogue was capable of self-assembly leading to hydrogel formation. However, we found that the depsipeptide did not possess an affinity for the protein high enough to influence cell behavior in the same manner as the peptide. These results suggest that backbone amide hydrogen bonding is crucial in mediating RGD-integrin interaction affinity. Based on these results and other studies in the literature suggesting that amide-to-ester mutations have a complex and context-dependent effect on peptide-protein interactions, further development of depsipeptide-based materials should focus on exploring alternate N-protecting groups that are likely to have higher biocompatibility while driving robust self-assembly, exploring in more depth the ability to tune degradation rates and mechanical properties using alternate side chain chemistries, and exploiting depsipeptide self-assembly and degradability for non-viral gene delivery.