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Date of Award
Jennifer L. Stockdill
Disulfide bonds are an important structural feature in many peptides. Controlled disulfide bond formation is often the limiting step for accessing the native structure of disulfide-rich peptides. Traditionally, disulfide-rich peptides are folded by either thermodynamic control under oxidative conditions, or orthogonal deprotection using commercially-available cysteine derivatives. These approaches can be effective means of folding, but are often insufficient for complex peptides with several disulfide linkages. In my thesis work, strategies to facilitate the efficient and accurate folding of disulfide rich peptides were pursued using conotoxins as model peptide targets. Conotoxins are a class of medically-interesting disulfide-rich peptides that have shown excellent activity as selective ion channel inhibitors. Development of single reaction vessel conditions that couple thiol deprotection and in situ oxidation to form the desired disulfides were realized through the design and synthesis of new palladium-labile protecting groups. Novel protection strategies enabled the step-wise, regioselective on-resin synthesis of neuroactive peptides oxytocin, α-conotoxin LvIA, and α-conotoxin ImI. Ellman’s reagent was successfully and simultaneously employed for visual reaction monitoring and disulfide bond formation in resin-bound peptides. A series of structurally-related and pseudo-orthogonal protecting groups were synthesized and implemented in a kinetically-controlled method for sequential disulfide formation. Overall, the work discussed herein extends the chemical toolbox available for the controlled synthesis of disulfide-rich peptides.
Saraha, Hasina, "Strategies For Controlled Disulfide Formation To Access Neuroactive Conotoxins And Investigation Of Novel Palladium-Labile Cysteine Protecting Groups" (2018). Wayne State University Dissertations. 2064.