Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro.
The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.
Gosselin
G
G
Laboratoire de Chimie Bioorganique, URA Centre National de la Recherche Scientifique 488, Université de Montpellier II, Sciences et Techniques du Languedoc, France.
Schinazi
R F
RF
Sommadossi
J P
JP
Mathé
C
C
Bergogne
M C
MC
Aubertin
A M
AM
Kirn
A
A
Imbach
J L
JL
D000998:Antiviral Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D002460:Cell Line; D004351:Drug Resistance; D006678:HIV / Q000187:drug effects*; D006801:Humans; D013237:Stereoisomerism; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity
D000998:Antiviral Agents; C085719:2',3'-dideoxy-beta-5-fluorocytidine; D016047:Zalcitabine