A unique series of simple "unnatural" nucleosides has been discovered to inhibit hepatitis B virus (HBV) replication. Through structure-activity analysis it was found that the 3-OH group of the -L-2-deoxyribose of the -L-2-deoxynucleoside confers specific antihepadnavirus activity. The unsubstituted nucleosides -L-2-deoxycytidine, -L-thymidine, and -L-2-deoxyadenosine had the most potent, selective, and specific antiviral activity against HBV replication. Human DNA polymerases (␣, , and ␥) and mitochondrial function were not affected. In the woodchuck model of chronic HBV infection, viral load was reduced by as much as 10 8 genome equivalents/ml of serum and there was no drug-related toxicity. In addition, the decline in woodchuck hepatitis virus surface antigen paralleled the decrease in viral load. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.Infection with hepatitis B virus (HBV) is a major world health problem, affecting 5% of the population. More than 2 billion people have been infected with the virus, and 350 million of them are chronic carriers at risk of death from cirrhosis and liver cancer (49).Several strategies have been evaluated for the treatment of chronic HBV infection with the goal of eliminating persistent viral replication and preventing progression to chronic active hepatitis and liver failure. Currently, the only approved treatment options are alpha interferon (IFN) and lamivudine (-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine [3TC]). Unfortunately, the rate of response to IFN is low, and drug-associated side effects are significant (24,55). Individuals who are immunosuppressed (e.g., transplant recipients or those coinfected with the human immunodeficiency virus [HIV]) rarely respond to IFN therapy (13). Lamivudine is a well-known example of the class of -Lnucleoside analogs that has recently drawn attention as antiviral and anticancer agents (52). As with IFN, however, a complete antiviral response, as assessed by HBe seroconversion, is seen in only a minority of patients after 1 year of treatment (27). In addition, cessation of lamivudine therapy or development of viral resistance may lead to a marked rebound in viral replication which can be life threatening (hepatitis flare) in HIV-HBV-coinfected patients (2, 30). Lamivudine resistance is now recognized in 16 to 32% of HBV-infected patients after 1 year of treatment and in as many as 58% after 2 to 3 years (14,27,30).Since the Food and Drug Administration approved lamivudine for the treatment of HIV infection in the United States in 1996 and for HBV in 1998, intensive studies on "unnatural" L-nucleosides as agents against HIV, HBV, and herpesviruses (including Epstein-Barr virus [EBV]) and as anticancer agents have been conducted (23). Now, through an extensive structure-activity analysis, we have found that the 3Ј-OH group of the -L-2Ј-deoxyribose of the -L-2Ј-deoxynucleoside series confers unique specificity for anti-HBV activity. In this ...
In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), and three flaviviruses, namely, yellow fever virus, West Nile virus, and dengue-2 virus. However, pharmacokinetic studies revealed that 2'-C-methylcytidine suffers from a low oral bioavailability. To overcome this limitation, we have synthesized the 3'-O-l-valinyl ester derivative (dihydrochloride form, valopicitabine, NM283) of 2'-C-methylcytidine. We detail herein for the first time the chemical synthesis and physicochemical characteristics of this anti-HCV prodrug candidate, as well as a comparative study of its pharmacokinetic parameters with those of its parent nucleoside analogue, 2'-C-methylcytidine.
Hepatitis B virus (HBV) is the major cause of acute and chronic hepatitis, leading to progressive development of necroinflammatory changes in the liver, which can result in cirrhosis and hepatocellular carcinoma (1, 7). Approximately 350 million people (5% of the world's population) are chronically infected with HBV, and 1 million of these patients die every year as a result of this infection (11). Although the development of an effective vaccine to prevent HBV infection has shown promising results and should lead to its eventual eradication, antiviral chemotherapy remains the only effective method to prevent the progression of the disease in chronic carriers (8). Initially, alpha interferon was used as therapy for chronic HBV infection; however, the majority of patients did not benefit, and side effects were significant in some patients (15). At present, -L-2Ј,3Ј-dideoxy-3Ј-thiacytidine (lamivudine) is the only nucleoside analogue approved for use for the treatment of chronic hepatitis B; however, upon the cessation of treatment serum HBV DNA levels return to pretreatment levels. This rebound is also associated with the appearance of drug-resistant virus that is mutated at the active site of the viral reverse transcriptase (9). Therefore, the development of new antiretroviral agents active against HBV is needed.Recently, -L-thymidine (L-dT) and -L-2Ј-deoxycytidine (LdC) were shown to be potent and specific inhibitors of HBV replication both in vivo and in vitro (50% effective concentrations [EC 50 s], 0.19 to 0.24 M in human hepatoma 2.2.15 cells) (2). In a phase I-II clinical trial, treatment with L-dT has also been demonstrated to cause marked reductions in HBV DNA levels in chronically infected patients
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