The development of novel compounds that can effectively inhibit both wild type and the most consensus resistant strains of human immunodeficiency virus type 1 (HIV-1) is the primary focus in HIV disease management. Combination therapy, comprising at least three classes of drugs, has become the standard of care for acquired immunodeficiency syndrome (AIDS) or HIV-infected individuals. The drug cocktail can comprise all three classes of HIV inhibitors, including nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). Due to their competitive mode of inhibition and requirement for metabolic activation, almost all NRTI drugs lack the virological potency of NNRTI or PI drugs. However, data from clinical trials indicate that sustained viral suppression could not be achieved with NRTI, NNRTI or PIs alone. Therefore, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, because they enhance the virological potency of the regimen, they do not bind excessively to protein and most regimens are small pills/tablets given once a day. It has become apparent in recent years that the prolonged use of certain NRTIs exhibits adverse events as a class, limiting the length of time for which they can be safely used. Of major clinical concern is their association with the potentially fatal lactic acidaemia and hepatic steatosis. These class events, as well as individual drug effects, such as peripheral neuropathy, are linked to delayed mitochondrial destruction. In addition to toxicity, the development of resistance-conferring mutations against exposure to nucleoside analogs currently in use influences long-term therapeutic benefits. Of critical importance for the evaluation of new NRTIs are recent studies showing that the efficiency of discrimination or excision by pyrophosphorolysis in the presence of nucleotides of a given NRTI is a key determinant in the emergence of one or the other resistance pathway.
-D-N4 -Hydroxycytidine (NHC) was found to have selective anti-hepatitis C virus (HCV) activity in the HCV replicon system (clone A). The intracellular metabolism of tritiated NHC was investigated in the HCV replicon system, Huh-7 cells, HepG2 cells, and primary human hepatocytes. Incubation of cells with 10 M radiolabeled NHC demonstrated extensive and rapid phosphorylation in all liver cells. Besides the 5-mono, -di-, and -triphosphate metabolites of NHC, other metabolites were characterized. These included cytidine and uridine mono-, di-, and triphosphates. UTP was the predominant early metabolite in Huh-7 cells and primary human hepatocytes, suggesting deamination of NHC as the primary catabolic pathway. The intracellular half-lives of radiolabeled NHC-triphosphate and of CTP and UTP derived from NHC incubation in Huh-7 cells were calculated to be 3.0 ؎ 1.3, 10.4 ؎ 3.3, and 13.2 ؎ 3.5 h (means ؎ standard deviations), respectively. Studies using monkey and human whole blood demonstrated more-rapid deamination and oxidation in monkey cells than in human cells, suggesting that NHC may not persist long enough in plasma to be delivered to liver cells.Hepatitis C virus (HCV) causes liver disease and is spread primarily by contact with the blood of an infected person. Globally, an estimated 170 million persons are chronically infected with HCV (20). An estimated 3.9 million Americans (1.8%) have been infected with HCV, and cirrhosis will eventually develop in at least 15 to 20 percent of them (1, 12). HCV is one of the most important causes of chronic liver disease and seems to progress more rapidly to liver damage in human immunodeficiency virus-infected persons than in noninfected persons (13). Interferon, alone and in combination with ribavirin, is approved for the treatment of persons with chronic hepatitis C. Treatment with interferon for genotype 1-infected individuals is effective in about 15 to 20% of patients (6, 16), but when combined with ribavirin, its effectiveness increases to almost 42%; ribavirin alone, however, is ineffective (6). The combination of ribavirin and interferon is 80% effective against genotypes 2 and 3 (12, 16). Therefore, we need to develop new antiviral agents active against all genotypes of HCV, particularly genotype 1, which is commonly found in the United States and China (11).-D-N 4 -Hydroxycytidine (NHC), a base-modified ribonucleoside analogue, was identified as a potent and selective anti-HCV candidate (19). In a bovine viral diarrhea virus infection system and in HCV replicon RNA in Huh-7 cells, NHC had 90% effective concentrations (EC 90 ) of 2 and 5 M, respectively (19). NHC was nontoxic (50% inhibitory concentration, Ͼ100 M) in the HCV replicon system (clone A cells, genotype 1b), Huh-7 cells, HepG2 cells, and human peripheral blood mononuclear cells (19). Levels of mitochondrial DNA and RNA or lactic acid in HepG2 cells treated with NHC did not change, suggesting no delayed toxicity (19). Although the antiviral mechanism of action of NHC is not completely understood, it...
The first synthesis of oligodeoxynucleotide heteropolymers carrying base-sensitive S-pivaloylthioethyl (t-Bu-SATE) phosphotriester linkages has been performed. It is based on the use of 6-nitroveratryloxycarbonyl (NVOC) and 2,2‘-bis(2-nitrophenyl)ethoxycarbonyl (diNPEOC) groups as nucleobase protections in combination with photolysis deprotection. The synthesis was realized using the phosphoramidite approach on solid support bearing a 1-(o-nitrophenyl)-1,3-propanediol linker. The removal of the protecting groups and the cleavage of the oligonucleotides from the solid support were accomplished in a single photolysis procedure upon UV irradiation at wavelengths >300 nm. Faster deprotection rates were observed for diNPEOC-protected nucleosides and oligomers than with NVOC-protected ones. The synthesis of pentanucleoside t-Bu-SATE-phosphotriesters d(5‘TpCpCpCpTp 3‘), d(5‘TpApApApAp 3‘), and d(5‘TpGpGpGpTp 3‘) and of dodecanucleoside t-Bu-SATE-phosphotriesters and -phosphorothioate d(5‘ApCpApCpCpCpApApTpTpCpTp 3‘) and d(5‘ApGpApApTpTpGpGpGpTpGpTp 3‘) demonstrated the efficiency of the method.
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