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Functional Polypeptides for Biomedical Applications

  • Author(s): Kramer, Jessica R.
  • Advisor(s): Deming, Timothy J
  • et al.
Abstract

Synthetic polypeptides have shown great promise as materials for biotechnology and medicine, with applications in tissue engineering, drug delivery, and as therapeutics. Despite significant advances in the preparation of well-defined polypeptides and the development of self-assembling materials, a need remains for a broader scope of polypeptides with functionalities that mimic the complexity and function of post-translationally modified natural proteins. The display of functionalities that have therapeutic effects, target materials to specific tissues, passivate the immune response, or have stimuli responsive behavior, are highly desirable yet generally require complex and inefficient synthetic approaches.

This dissertation reports several distinct advances in the preparation of a wide variety of highly functional polypeptide materials. Progress in both the polymerization of functionalized NCA monomers and the post-polymerization modification of polypeptides is described. A new method of NCA purification was developed, and has allowed access to diverse monomers with functionalities previously unattainable due to impurities that impeded polymerization. This purification technique was applied to the synthesis of glycosylated NCAs, which yielded the first living polymerizations of glycosylated NCAs and gave access to glycopolypeptides with unique properties and conformations. The display of sugar functionalities from synthetic polymers is an area of great interest due to the many attractive properties imparted upon the parent material, such as non-ionic water solubility, biological targeting, and shielding of the polypeptide from proteases. These glycopolypeptides were used to explore the effect of conformation on self-assembly and ligand binding, and to develop vesicles with potential medical applications in targeted drug delivery. In addition, a new conjugation technique for facile post-polymerization modification of polypeptides is described. This conjugation utilizes the unique chemistry of the natural amino acid methionine to allow chemoselective introduction of a wide variety of functional groups via alkylation. We investigated the stability of various alkylated methionines to thiolysis, and developed a simple method to attach and later remove different groups. Finally, work performed during an NSF-IGERT funded internship at HRL Laboratories Inc. is described. Surface modification of carbon foam anodes for microbial fuel cell applications was explored, and the use of thermogravimetric analysis as technique to evaluate biofilm formation was developed.

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