opioid, synthesis, peptide, addition, cyclic tetrapeptide
Amino Acids, Peptides, and Proteins | Biochemistry | Organic Chemistry
The opioid epidemic is a global epidemic that claims more lives every passing year. Previous research has shown that antagonism of the kappa opioid receptors (KOR) has potential in treating opioid drug addiction in mice. The cyclic tetrapeptide cyclo[Pro-Sar-Phe-D-Phe] has shown short-lived antagonism of the kappa opioid receptor at small doses (~0.03 nmol). It has also been shown to reduce the drug seeking behavior of mice following exposure to drug or stress in a conditioned place preference (CPP) assay. In prospect of increasing the half-life of the tetrapeptide, we systematically varied the prolyl residue of cyclo[Pro-Sar-Phe-D-Phe] to investigate the structure-activity relationship of the peptide, namely the role of hydrogen bonding sites, alpha carbon and amide nitrogen alkylation, and peptide cis-trans isomerization. The linear precursors were synthesized by solid-phase peptide synthesis (SPPS) and were subsequently cyclized in solution to yield the desired analogs. The cyclic peptides were then purified via normal-phase then reverse-phase column chromatography. Once purified, the peptides were identified by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS) and high performance liquid chromatography (HPLC). Necessary work that is needed to be completed in the future is to cyclize, to purify and to identify the remaining tetrapeptide analogs and send off for testing in mice to determine the effects of kappa antagonism and half-life of the peptides.
Department 1 Awarding Honors Status
Cellini, J. (2020). Progress towards the synthesis of analogs of the cyclic opioid tetrapeptide cyclo[Pro-Sar-Phe-D-Phe] (Undergraduate honors thesis, University of Redlands). Retrieved from https://inspire.redlands.edu/cas_honors/1001
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