Conversion of 2',3'-dideoxyadenosine (ddA) and 2',3'-didehydro-2',3'- dideoxyadenosine (d4A) to their corresponding aryloxyphosphoramidate derivatives markedly potentiates their activity against human immunodeficiency virus and hepatitis B virus

Jan Balzarini, Johannes Kruining, Orson Wedgwood, Christophe Pannecouque, Stefano Aquaro, Carlo Federico Perno, Lieve Naesens, Myriam Witvrouw, Rudolf Heijtink, Erik De Clercq, Christopher McGuigan

Research output: Contribution to journalArticlepeer-review

Abstract

2',3'-Dideoxyadenosine (ddA), 2',3'-didehydro-2',3'-dideoxyadenosine (d4A) and their lipophilic 5'-monophosphate triester (aryloxyphosphoramidate) prodrugs were evaluated for their anti-retrovirus and anti-hepatitis B virus activity in various cell culture models. The aryloxyphosphoramidate derivatives of ddA (Cf 1093) and d4A (Cf 1001) showed markedly superior (100- 1000-fold) efficacies than the parent drugs against human immunodeficiency virus type 1 (HIV-1), HIV-2, simian immunodeficiency virus (SIV), Moloney murine sarcoma virus (MSV) and human hepatitis B virus (HBV) replication regardless of the cell type in which the virus replication was studied (i.e., human T-lymphocyte CEM, MT-4, Molt/4 and C8166 cells, peripheral blood lymphocytes (PBL), monocyte/macrophages (M/M), murine embryo fibroblasts and human hepatocyte cells). Also the selectivity index (ratio of cytotoxic concentration/antivirally effective concentration) of both aryloxyphosphoramidate prodrugs was markedly increased. In particular the d4A prodrug Cf 1001 showed a selectivity index of 300-3000 as compared with 23 for the parental d4A in established laboratory cell lines. Also Cf 1001 had a selectivity index of 400-650 in HIV-1-infected PBL and M/M, respectively. Both Cf 1001 and Cf 1093 were equally efficient as 3TC (lamivudine) in inhibiting HBV replication in hepatocytes, and rank among the most potent HIV and HBV inhibitors reported so far in cell culture.

Original languageEnglish
Pages (from-to)324-328
Number of pages5
JournalFEBS Letters
Volume410
Issue number2-3
DOIs
Publication statusPublished - Jun 30 1997

Keywords

  • AIDS
  • HBV
  • Hepatitis
  • HIV
  • Nucleoside analogues
  • Prodrugs
  • Reverse transcriptase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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