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 ...
2',3'-Dideoxynucleosides (ddNs) including 3'-azido-3'-deoxythymidine (AZT), 3'-fluoro-3'-deoxythymidine (FLT), 3'-amino-3'-deoxythymidine (AMT), 2',3'-dideoxycytidine (ddC), and 2',3'-didehydro-3'-deoxythymidine (D4T) were tested for their effects on proliferation and differentiation of pluripotent progenitor cells (CD34+) purified from human bone marrow cells grown in liquid cultures. These highly purified progenitor cells undergo extensive proliferation during 14 days, with a marked differentiation during the last 7 days. These differentiated cells exhibit normal morphological features in response to specific hematopoietic growth factors of both erythroid and granulocyte-macrophage lineages, as demonstrated by flow cytometry cell phenotyping. The potencies of these ddNs in inhibiting proliferation of granulocyte-macrophage lineage cells were in the order FLT > AMT = ddC > AZT > D4T, and the potencies in inhibiting proliferation of erythroid lineage cultures were in the order FLT > AMT > AZT > ddC > D4T. The toxic effects of ddNs assessed in these liquid cultures were in agreement with data obtained by using semisolid cultures, demonstrating the consistency of these two in vitro hematopoietic systems toward ddN toxicity. ddC was toxic to CD34+ progenitor cells and/or cells in the early stages of differentiation, whereas the inhibitory effect of AZT on the erythroid lineage was predominately observed on a more mature population of erythroid progenitors during the differentiation process. Slot blot analysis of granulocyte-macrophage cultures demonstrated that exposure to ddC and FLT was associated with a decrease in total mitochondrial DNA (mtDNA) content, suggesting that these two ddNs inhibit mtDNA synthesis. In contrast, no difference in the ratio of nuclear DNA to mtDNA was observed in cells exposed to toxic concentrations ofAZT and AMT, demonstrating that the bone marrow toxicity induced by AZT and its metabolite AMT is not associated with an inhibition of mtDNA synthesis. This human pluripotent progenitor liquid culture system should permit detailed investigations of the cellular and molecular events involved in ddN-induced hematological toxicity.The thymidine analog 3'-azido-3'-deoxythymidine (AZT) was the first drug approved for the treatment of AIDS. AZT has been demonstrated to induce immunological improvement, decrease the incidence of opportunistic infections, and reduce mortality from AIDS (15, 42). The major limitation to AZT therapy is bone marrow toxicity, manifested as anemia and neutropenia (30). Our laboratory was the first to demonstrate that direct exposure of human bone marrow cells to AZT in vitro effected a dose-dependent inhibition of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) (33). While these clonogenic assays with human bone marrow mononuclear cells in semisolid medium have been shown to be an adequate model for predicting the cytotoxicity of antiretroviral compounds to bone marrow cells (32), the semisolid nature of the assay and the low cloning effi...
through in vitro selection with 3TC or FTC (11,12,23). DNA sequence analysis of the RT gene amplified from a patient who had received 3TC therapy for 4 months revealed a mixture of the mutation at codon 184 from Met to Val (M184V) and the parental genotype, indicating that the mutation at the methionine at codon 184 (Met-184) can occur in vivo (23). In order to understand the mechanisms of action and drug resistance, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (LFddCTP) were synthesized, and the inhibitory effects of these triphosphate derivatives toward HIV-1 RT recombinant wildtype (WT) (WT RT) and the site-directed mutagenesis recom-
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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