UCLA

Synthetic polypeptides are protein-mimetic materials that have been studied intensely for their potential biomedical applications. Advancements in polypeptide synthesis and peptide chemistries have enabled the design of structurally diverse biomaterials for a wide-range of applications. Their peptide bond backbone imbues the polymers with excellent biocompatibility while the relationship between amino acid residue and backbone structure permits the design of highly organized, supramolecular structures for biological applications. This dissertation describes recent advancements in synthetic polypeptides preparation, incorporation of non-standard amino acids, and the design of stimuli-responsive materials in Chapter 1. The promise of synthetic polypeptides for the biomedical field and development of new biomaterials is demonstrated throughout this dissertation. Chapter 2 describes the preparation of poly(L-homoserine), SH, a non-ionic, water-soluble polypeptide for use in diblock copolypeptide assemblies. Characterization of SH properties revealed a disordered conformation that was maintained with increasing molecular weight, physiologically relevant ionic strength, and across a wide range of pH. The preparation of poly(L-homoserine)-b-poly(L-serine) amphiphilic diblock copolypeptides resulted in ordered assembly into unilamellar vesicles, highlighting the potential of SH as a water-solubilizing segment for biomaterial design. Chapter 3 describes the first successful synthesis of high molecular weight poly(dehydroalanine), ADH, via a soluble poly(L-cysteine) precursor. The unique α,β-unsaturation of the planar dehydroalanine residues made ADH an intriguing target for conformational studies and side-chain chemistries for further modification. Investigations into the preferred conformation of ADH revealed a new “hybrid coil” containing aspects of both a 25-helix and 310-helix in the solid and solution state. The soluble poly(L-cysteine) precursor allowed preparation of ADH-containing statistical and diblock colypeptides that are highly reactive towards amine and thiol nucleophiles, which provide a useful functional handle for the introduction of biologically relevant moieties. Adding to the intrigue of ADH, characterization of the homopolymer spectroscopic properties reveal an extraordinary blue fluorescence, potentially useful for the design of label-free fluorescent biomaterials for imaging applications. Chapter 4 focuses on the design of PEG-b-polypeptide based complex coacervate core micelles, C3Ms, for oligonucleotide delivery. Pegylated cationic, α-helical poly(S-alkyl-L-homocysteine) copolymers were prepared and characterized for single-stranded oligonucleotide complexation and release. Optimization of the copolymer composition and length resulted in highly stable, nano-scale C3Ms when complexed with poly(adenylic acid), poly(A). Characterization of the poly(A)-C3Ms revealed a monomodal size distribution with excellent poly(A) encapsulation efficiency, (>90%). The stimuli-responsive nature of the poly(A)-C3Ms was showcased by triggering release of the oligonucleotide cargo in the presence of other multivalent anions and basic pH.