Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation

Jagadeesh Nagendra Manda, Milica Markovic, Ellen M. Zimmermann, Shimon Ben-Shabat, Arik Dahan, Aaron Aponick

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A2 (PLA2), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA2-catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine-tuning. This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.

Original languageEnglish
Pages (from-to)1639-1644
Number of pages6
JournalChemMedChem
Volume15
Issue number17
DOIs
StatePublished - 3 Sep 2020

Keywords

  • cyclosporine
  • inflammatory bowel disease (IBD)
  • phospholipid-drug conjugates
  • prodrugs

ASJC Scopus subject areas

  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Molecular Medicine
  • Biochemistry
  • Pharmacology
  • Organic Chemistry

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