Author Type

Graduate Student

Date of Award

Spring 4-4-2021

Document Type

Thesis

Publication Status

Version of Record

Degree Name

Master of Science (MS)

Department

Biological Sciences

First Advisor

Predrag Cudic

Abstract

In this project we modified Odorranalectin (OL), a naturally occurring cyclic peptide, by the insertion of a somatostatin analogue sequence (CTOP), a known μ opioid receptor antagonist. The μ opioid receptor is the main target for many highly addictive opioids such as fentanyl, morphine, and heroin, and is associated with physical dependence, as well as respiratory depression, the main cause of overdose death. OL has lectinomimic properties that allow it to bind to oligosaccharides expressed on the olfactory nerves, facilitating its transport to the brain after intranasal administration. These characteristics make OL a promising platform for delivery of variety of small molecule or peptide drugs to the brain. In the final synthetic step, the targeted bicyclic OL-CTOP was prepared by cyclization of the linear resin-peptidyl precursor via disulfide bonds formation. The disulfide bond formation was optimized by changing the oxidizing agent, molar equivalents, and dimethyl sulfoxide (DMSO)/dimethyl formamide (DMF) solvent ratio. Through this investigation, the required amount of Iodine (I2) and oxidation time for both disulfide bonds in OL-CTOP were established. In addition, our data suggests that DMSO does not have an effect on cysteine oxidation. Last, it was determined that two disulfide bridges could be oxidized in one single oxidation step to obtain the correct bicyclic peptide configuration, significantly simplifying Solid-Phase Peptide Synthesis (SPPS) of this structurally complex peptide. The optimized cysteine oxidation reaction may have broader application to SPPS synthesis of variety of bi-cyclic peptides.

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