Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Brian Dominy, Committee Chair

Committee Member

Modi Wetzler, Co-Chair

Committee Member

William Pennington

Committee Member

Gautam Bhattacharyya

Abstract

The conjugation of poly(ethylene glycol) (PEG) to peptides is known to increase serum stability of peptides and long polydisperse PEGs have been used for decades as a strategy to improve pharmacokinetic profiles of protein therapeutics. However, the effects of PEGylation on the conformational stability and protease resistance of peptides will unpredictably vary depending on 1) site(s) of PEGylation, 2) conjugation strategy, 3) chain length, as well as 4) chain branching. Site-specific PEGylation of peptides requires the use of cumbersome protecting groups and, when performed at lysines, often transforms the amine into an amide. To facilitate both fundamental and applied studies of peptide PEGylation, the current toolbox needs to be expanded. Analogues of glutamine and lysine incorporating a linear PEG or branched di- and triPEG side chains have been synthesized using several synthetic approaches. Additionally, biotin and fluorescein have been covalently attached to the N-epsilon-position of lysine that is bifunctionalized with a single linear N-epsilon-PEG chain. Additionally, many of the synthesized PEG amino acids have been site-specifically incorporated into biologically relevant peptide sequences. These PEG-amino acid monomers can be directly incorporated into solid phase peptide synthesis to study their effects on peptide folding energetics (conformational stability) and ultimately to further enhance pharmacokinetic properties of PEGylated peptide drugs. The bulkier nature of the novel branched PEG amino acids can potentially be used to help solubility in aqueous environments or repel macromolecules from a peptide cleavage site. Additionally, this strategy should be useful for the generation of single- and multi-site selectively PEGylated peptides for therapeutic applications. Due to a growing interest in peptidomimetics for their potential applications in the pharmaceutical industry, two classes of peptidomimetics were investigated: Freidinger lactams and peptoids. Freidinger lactams were originally designed as a conformationally constrained dipeptide that could be used to lock a synthetic peptide into a bioactive conformation; however, the current synthetic approach is typically low yielding and limits functionalization. An improved synthetic route to Freidinger lactams was developed that allows for chirality off the N-delta-position. Peptoids, unlike peptides, have side chains appended to the backbone nitrogen instead of the alpha-carbon; a structural change that makes them more stable to proteolysis. A small library of antimicrobial peptoids with varying aliphatic, cationic, and aromatic side chains have been designed and synthesized.

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