Date of Award

2018-01-01

Degree Name

Doctor of Philosophy

Department

Chemistry

Advisor(s)

Katja Michael

Abstract

Since the introduction of solid phase peptide synThesis in 1963, peptides and post-translationally modified peptides can be conveniently synthesized in the chemistry laboratory. In the past decade, there has been a remarkable increase in bioactive peptide research and the therapeutic peptide market value is expected to hit $25 billion this year. Peptides can also provide structural and biological functions and have emerged as promising novel biomaterials in tissue engineering. Here we will describe three different projects, which deal with different aspects of peptide chemistry, i.e. synthetic method development, exploration of new peptide biomaterials, and the use of cell penetrating peptides in medicinal chemistry research. Specifically, the aims of this Dissertation were 1) to optimize the synThesis of a photoreactive linker and photoreactive amino acids for solid phase peptide synThesis; 2) to synthesize photoreactive collagen-like peptides (CLPs) and to study their photochemical properties; and 3) the syntheses of potential anti-leishmanial compounds and their conjugation to a cell-penetrating peptide in an attempt to improve their bioavailability.

In this Dissertation we demonstrate the optimized synThesis of a dual functional linker previously developed in our laboratory and its use in the synThesis of photoreactive amino acid building blocks and in the synThesis of photoreactive peptides. We also show the incorporation of photoreactive amino acids into the backbone of a collagen peptide, its capability to undergo one-photon as well as two-photon photolysis, and its potential usefulness in biophotolithography. Furthermore, the synThesis of a second generation photoreactive CLP with cross-linking capabilities for the production of rigid hydrogels is presented. This photoreactive collagen-like peptide is a new biomaterial with potential future applications in tissue engineering. Lastly, anti-leishmanial compounds were synthesized, as well as the cell-penetrating peptide "TAT", with several copies of the anti-leishmanial compound covalently linked to it. Unexpectedly, dose response curves against Leishmania major promastigotes show that the anti-leishmanial compounds alone have a significantly greater anti-parasitic activity compared to their TAT conjugated counterparts. While conjugation to the TAT peptide resulted in a decreased toxicity toward mammalian cells, our results show that improving a bioactive compound's water solubility and membrane permeability may not necessarily result in greater bioactivity, but can even be detrimental.

Language

en

Provenance

Received from ProQuest

File Size

256 pages

File Format

application/pdf

Rights Holder

Alfredo Ornelas

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Included in

Chemistry Commons

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