Mini-reviewl-Nucleoside enantiomers as antivirals drugs: A mini-review
Introduction
The current armamentarium for the chemotherapy of viral infections is the result of several decades of research, including syntheses and biological evaluations of nucleoside analogues (De Clercq, 2005a). In the search for antiviral nucleoside analogues, structural modifications of the heterocyclic bases and/or modifications on the sugar moiety of natural nucleosides can be attempted. In the latter, the main modifications involved changes in the (2-deoxy)-d-ribofuranose moiety like, inversion of hydroxyl group configurations, their elimination leading to dideoxy- or dideoxy-didehydro-nucleosides, their substitution/functionalisation by various synthetic groups, or cleavage of the sugar ring leading to acyclic nucleosides. Other structural modifications have also been attempted such as replacement by a methylene group or a sulfur atom of the endocyclic oxygen, transposition of the latter and/or additional insertion of a second heteroatom in the sugar moiety (Mansour and Storer, 1997). Currently, nucleoside analogues are prominent drugs in the management of several viral infections, including HSV, HIV, HBV, HCV and HCMV infections (De Clercq, 2005b). The nucleoside analogues at present formally approved for the treatment of viral infections are shown in Fig. 1.
The mechanism of action of nucleoside analogues is based upon the intracellular phosphorylation to their 5′-triphosphate form which can interact with virus-specific polymerases, acting as a competitive inhibitor or an alternate substrate for these target enzymes, usually preventing further viral nucleic acid chain elongation. For a long period, it was assumed that nucleoside analogues having only a natural d-configuration, by analogy with the natural ones, could exhibit biological activity, owing to the believed stereospecificity of enzymes in living systems (Focher et al., 2003, Maury, 2000). In the beginning of the 90 s, this assumption was reevaluated, and l-nucleoside enantiomers (which are non-superimposable mirror images of the natural d-nucleosides, like the right and left hands) emerged as a new class of antiviral agents. Although the first synthesis of a l-nucleoside was reported in 1964 (Smejkal and Sorm, 1964), little attention was paid to l-nucleoside analogues until the discovery of lamivudine (3TC, Fig. 1) (Cameron et al., 1993, Jarvis and Faulds, 1999). Since then, a large number of l-nucleoside analogues have been synthesized and their antiviral activities evaluated (Furman and Painter, 1995, Nair and Jahnke, 1995, Wang et al., 1998, Graciet and Schinazi, 1999, Zemlicka, 2000, Cheng, 2001, Gumina et al., 2001, Gumina et al., 2002). From this tremendous work, it appears that favorable features of l-nucleoside analogues may include an antiviral activity comparable and sometimes greater than their d-counterparts, more favorable toxicological profiles and a greater metabolic stability. In this mini-review, we will summarize briefly biological features and the current status of the l-nucleosides currently undergoing clinical trials and/or preclinical studies as antiviral agents.
Section snippets
l-Nucleoside analogues as anti-HCMV agents
Infections by herpes viruses are among the most common and easily transmitted viral diseases in man. Numerous distinct herpes viruses have been identified and the treatment by therapeutic agents of diseases caused by some of them has produced clinical benefits. Human cytomegalovirus (HCMV) is one of the eight human herpes viruses that cause widespread infections. Currently, in the United States, more than 40% of the population is infected with HCMV (Sia and Patel, 2000). Normally, in healthy
l-Nucleosides as anti-HBV agents
According to the World Health Organization, over 350 millions people (≈5% of the world population) are chronically infected with hepatitis B virus (HBV). HBV infection induces a spectrum of disease ranging from mild, asymptomatic infection to severe chronic liver diseases, including cirrhosis and hepatocellular carcinoma. Although safe and effective vaccination for HBV is available for developing countries, there is still a need for effective treatment for the millions of chronically infected
Other l-nucleoside analogues of interest as potential antiviral agents
Emtricitabine (Fig. 1), which is marketed by Gilead (http://www.gilead.com) as Emtriva® in combination with other antiretroviral agents for the treatment of HIV infection in adults, is currently in clinical trials in order to evaluate its potency for the treatment of chronic hepatitis B (Saag, 2006).
Another 5-fluoro-l-cytosine nucleoside analogue (elvucitabine, 2′,3′-didehydro-2′,3′-dideoxy-β-l-5-fluorocytidine, Fig. 2), has also shown potent in vitro activity against HIV and HBV (Chen, 2002).
Conclusion
Drug discovery in antiviral chemotherapy has provided effective treatments for various viral infections. In particular, nucleoside analogues have been the cornerstone of antiviral treatments for several decades. In the search for new, safe and effective agents within this class, l-nucleoside enantiomers represent an immense breakthrough. As a general feature, those compounds with an unnatural configuration confer in most cases lower toxicity and higher metabolic stability compared to the
Acknowledgement
We are indebted to Dr. R. Storer (Idenix) for critically reading the manuscript.
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