Bioreversible disulfide linkage of thioamide compounds to thiol-poly(ethylene glycol): Application to UC781, an inhibitor of HIV-1 reverse transcriptase

Guobao Zhang, Bo Qiu, Barbara A. Perry, Denise E. Georgopoulos, Michael J Leibowitz, Patrick J. Sinko, Stanley Stein

Research output: Contribution to journalArticle

Abstract

To take advantage of the inherent properties of poly(ethylene glycol) (PEG) as a carrier for lowmolecular weight drugs, we developed a novel approach to produce a water-soluble (>3 mg/ml) prodrug form of UC781, an otherwise water-insoluble inhibitor of HIV-1 reverse transcriptase. In our process, UC781, which contains the thioamide grouping, was first oxidized to the disulfide-linked homodimer, which was then reacted with thiol-PEG in an exchange reaction to give the desired product, PEG-S-S-UC781. Release of the parent drug UC781 from its PEG-conjugate by mild reductive cleavage was found to occur both in vitro and in vivo. Normal saline, instead of dimethylsulfoxide could be used as the diluent for intravenous injection.

Original languageEnglish (US)
Pages (from-to)46-53
Number of pages8
JournalJournal of Applied Therapeutic Research
Volume4
Issue number4
StatePublished - 2004
Externally publishedYes

Keywords

  • Bovine serum albumin
  • BSA
  • DCM
  • Dichloromethane
  • DIEA
  • Diisopropyl ethylamine
  • Dimethylformamide
  • Dimethylsulfoxide
  • Dithiothreitol
  • DMF
  • DMSO
  • DTT
  • PBS
  • PEG
  • Phosphate-buffered saline
  • Poly(ethylene glycol)
  • Reverse transcriptase
  • RT
  • TCA
  • Trichloroacetic acid
  • UC781

ASJC Scopus subject areas

  • Pharmacology

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