Antiviral activity of 2′,3′-dideoxy-β-L-5-fluorocytidine (β-L-FddC) and 2′,3′-dideoxy-β-L-cytidine (β-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro

Abstract

2′,3′-Dideoxy-β-L-5-fluorocytidine (β-L-FddC) and 2′,3′-dideoxy-β-L-cytidine (β-L-ddC), two nucleosides with “unnatural L-configuration,” have been synthesized and found to have potent antiviral activity against hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HTV-1) in vitro with very little toxicity. At 1 μM, both β-L-ddC and β-L-FddC inhibited the growth of HBV by more than 90%, while at the same concentration the D-configuration counterparts, 2′,3′-dideoxy-β-D-cytidine (ddC) and 2′,3′- dideoxy-β-D-5-fluorocytidine (β-D-FddC), did not show antiviral activity against HBV. The order of anti- HIV-1 activity was β-L-FddC > ddC; β-D-FddC > β-L-ddC. The dose-limiting toxicity of ddC is neuropathy which is believed to be caused by the inhibition of the synthesis of mitochondrial DNA. ddC severely inhibited the mitochondrial DNA synthesis of CEM cells yielding an IC50 value of 0.022 μM. Conversely, both β-L-FddC and β-L-ddC did not demonstrate any inhibition against mitochondrial DNA synthesis up to 100 μM concentration.