PEGylation of Octreotide Using an α,β-unsaturated-β′-mono-sulfone Functionalized PEG Reagent

Authors

  • Abbas Shafiee Department of Medicinal Chemistry,Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Alireza Foroumadi Drug Design and Development Research Center,Tehran University of Medical Sciences, Tehran, Iran. Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Fatemeh Atyabi Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Nanotechnology Research Centre,Tehran University of Medical Sciences, Tehran, Iran
  • Laleh Erfani-Jabarian Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Reza Rouini Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Drug Design and Development Research Center,Tehran University of Medical Sciences, Tehran, Iran.
  • Mohsen Amini Drug Design and Development Research Center,Tehran University of Medical Sciences, Tehran, Iran. Department of Medicinal Chemistry,Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Negar Mohammad hosseini Drug Design and Development Research Center,Tehran University of Medical Sciences, Tehran, Iran. Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Rasoul Dinarvand Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Nanotechnology Research Centre,Tehran University of Medical Sciences, Tehran, Iran.
Abstract:

PEGylation is a well-established technique utilized to overcome the problems related to the therapeutic applications of peptides and proteins. Reasons for the PEGylation of these biological macromolecules include reducing immunogenicity, proteolytic degradation and rapid clearance from blood circulation. Octreotide is an octapeptide analogue of naturally-occurred somatostatin. This peptide has elimination half-life of less than 2 h that requires frequent daily subcutaneous or intravenous administration. To address this issue, octreotide modification was investigated using bis-thiol alkylating PEG reagent. The required bis-thiol alkylating reagent (V) was prepared from commercially available 4-acetyl benzoic acid in five steps. Octreotide disulfide bond was mildly reduced to liberate the two cysteine sulfur atoms followed by bis-alkylation to form PEGylated peptide. The PEG modification process was monitored through the reverse phase HPLC and 1H-NMR analysis. According to the HPLC chromatograms of PEGylation reaction, the peak with 30 min retention time was identified to be PEG-octreotide. In addition, 1H-NMR analysis showed a 7.44% degree of PEG substitution.

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Journal title

volume 11  issue 3

pages  747- 753

publication date 2012-06-12

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