UCLA

Functionalized polypeptides provide access to unique biomaterials that can be varied by the identity of the amino acid side chain; however, access to highly functionalized polypeptides is limited by the routes for sidechain modification. Modification of the polypeptide side chain requires careful post polymerization modification to ensure quantitative functionalization or the synthesis and stringent purification of functionalized monomers. The Deming group recently developed methods for the synthesis of high molecular weight poly(dehydroalanine) (ADH), which possesses reactive electrophilic groups that allows its efficient modification to functionalized polypeptides after reactions with thiol and amine nucleophiles. In this dissertation, I will detail the synthesis and characterization of various biomaterials derived from functionalized ADH polypeptides.Chapter 2 describes the synthesis and characterization of amino acid-functionalized poly(S-alkyl-rac-cysteines) polypeptides. These polypeptides possessed the ability to form coacervates with a variety of anions and ssRNA under physiological conditions. Furthermore, these coacervates could be tuned to respond to environmental stimuli, such as temperature, pH, and redox conditions to trigger coacervation formation and dissolution.Chapter 3 describes the synthesis and characterization of amphiphilic poly(L-methionine sulfoxide)x-b-poly(dehydroalanine)y, di-block copoly-peptides, MOxADHy, and their self-assembly into submicrometer-diameter unilamellar vesicles in aqueous media. The formation of vesicles was observed over an unprecedented range of copolypeptide compositions due to the unique properties and chain conformations of the ADH hydrophobic segments. These copolypeptides incorporate two distinct thiol reactive components where each segment can respond differently to a single thiol stimulus, allowing for in situ inversion of the vesicle assemblies and vesicle disruption via glutathione under intra-cellular mimetic conditions.Chapter 4 details the assembly and characterization of MOxADHy copolypeptides to form membranes that provide plasticity and selective permeability in aqueous mixtures, which allows predictable control of vesicle shape by variation of dialysis conditions. These findings expand upon vesicle shape transformation methods for biodegradable and thiol responsive polypeptide vesicles, which are amenable to development for applications in therapeutic delivery.Chapter 5 describes the synthesis and characterization of racemic mucin analogues bearing native glycans from the functionalization of ADH with un-protected thiol modified monosaccharides. Functionalization of ADH resulted in the formation of glycosylated poly(rac-cysteine) polypeptides, with no unnatural sidechain modification and high saccharide conjugation.