Comparative evaluation of L-Fd4C and related nucleoside analogs as promising antiviral agents.

As documented in the recent literature, there are more than 50 million people infected with HIV worldwide to date since the emergence of HIV and AIDS in the Western world in 1981. More importantly, about 7000 people die of AIDS daily with 2.5 and 2.6 millions total deaths in 1998 and 1999, respectively. On the other hand, human hepatitis B virus (HBV) is the leading cause of chronic hepatitis in the world. According to WHO executive summary, over 350 millions (approximately 5% of the world s population) people are chronically infected with HBV. There are about 1 million chronic HBV carriers in the United States. Although safe and effective vaccination for HBV is available for developing countries, there is still no effective treatment for the millions of chronically infected individuals. Consequently, long term infection with chronic HBV could lead to cirrhosis, and hepatocellular carcinoma. In light of these facts, it is evident that the discovery and development of novel antiviral agents for the treatment of HIV and HBV is an extremely important undertaking.The interest in L-nucleosides was spurred in recent years by the findings that L-nucleosides are generally endowed with lower host toxicity while maintaining good antiviral activity in comparison to their respective D-nucleosides. The recent FDA approval of Lamivudine [L-BCH 189 (3TC)] for the treatment of HIV and HBV further supports these notions. Since the discovery of Lamivudine, a large number of 2 ,3 -dideoxy (dd)- and 2 ,3 -didehydro-2 ,3 -dideoxy (D4)-L-nucleoside analogs have been synthesized and evaluated in hopes of identifying even better antiviral agents. As a result, 2 ,3 -Dideoxy-2 ,3 -didehydro-beta-L-fluorocytidine (beta-L-Fd4C) was found to be a promising new lead. The first synthesis and antiviral activity assessment of L-Fd4C were reported by Lin and Cheng et al. in 1996. Recent disclosures from several laboratories clearly demonstrated that L-Fd4C was the most potent anti-HBV agent reported to date (vs. 3TC, L-FddC, L-FMAU, etc.). In fact, L-Fd4C proved to be at least 10 times more potent than Lamivudine on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15. Compared with L-Fd4C, D-Fd4C showed similar anti-HIV activity yet reduced anti-HBV activity. 2 F-L-Fd4C exhibited excellent acid stability but reduced antiviral activity and cytotoxicity. Although L-Fd4C is converted intracellularly by cytoplasmic deoxycytidine kinase to its mono-, di- and triphosphate metabolites,43 the newly prepared bis(SATE)-L-Fd4CMP proved to be more potent against HBV yet less cytotoxic than L-Fd4C itself. The chemically synthesized L-Fd4CTP was found to be a poor substrate for human polymerase gamma. A recent report from Zhu and Cheng et al. indicated that L-Fd4C had no inhibitory effect on mitochondrial DNA synthesis at concentrations up to 10 microM. An in vivo study involving HBV-infected ducks showed that longer administration of L-Fd4C induced a sustained suppression of viremia (>95%) and of viral DNA synthesis in the liver. The same study also demonstrated that L-Fd4C is more potent than 3TC in vivo. In summary, on the basis of the data presented in this chapter, it is evident that L-Fd4C is endowed with exceptional anti-HBV activity (both in vitro and in vivo) as well as an acceptable toxicity profile, thus rendering it a very promising development candidate.