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With approximately 240 million chronically infected people, hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma in the world. Chronic HBV infection should be treated with antivirals, if either liver cirrhosis with detectable HBV DNA or relevant viral load (HBV DNA 2000 IU/ml) and signs of liver damage (transaminase elevation, fibrosis, risk of liver cancer or similar) are present. The current standard therapy is a long-term treatment with nucleoside or nucleotide analogues such as entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide, while in selected cases interferon treatment (for 48 weeks) may be useful. Entecavir and the new drug tenofovir alafenamide (TAF) are to be preferred over tenofovir disoproxil fumarate in patients with concomitant renal insufficiency or osteoporosis. Pregnant women with high viral load ( 200 000 IU/ml) should be treated with tenofovir in the third trimester to minimize the risk of neonatal transmission (in addition to immediate active-passive immunization). In conditions of immunosuppression (e. g. chemotherapy, rituximab, anti-TNF), even a "healed" HBV infection may reactivate in a life-threatening manner, requiring prophylactic antiviral therapy in addition to testing for HBV in high-risk situations. The current therapies primarily achieve virus suppression, but rarely the loss of HBs antigen, which is considered a functional cure. New strategies such as discontinuation of long-term antiviral therapy with provoked reactivation and also completely new drugs are currently in clinical trials. The most serious form of viral hepatitis is the co-/superinfection of HBV with the delta virus (HDV). Standard therapy for delta hepatitis is pegylated interferon-alfa, but the approval of new drugs such as the HBV entry inhibitor Myrcludex is expected in the near future.

Worldwide, hepatitis B virus (HBV) infection is among the 30 leading causes of death, despite effective vaccination and therapeutic options. Chronic hepatitis delta (coinfection with hepatitis D virus) leads to a rapid disease progression.Based on current international guidelines and studies, an overview about present and future therapeutic options for chronic hepatitis B and delta is provided.Therapy with nucleoside or nucleotide analogues leads to nearly complete HBV DNA suppression, which is associated with regression of liver fibrosis and a lower risk for the development of hepatocellular carcinoma. Therapy of chronic hepatitis delta with pegylated interferon alfa achieves only low response rates with high risk for virological relapse. Various therapeutic approaches are currently being investigated in preclinical and clinical studies and have led to a significant reduction of hepatitis B surface antigen (HBsAg) and HDV RNA.Current therapies of chronic HBV infection can effectively reduce subsequent complications. New therapeutic approaches promise functional cure (HBsAg loss) of HBV infection and effective treatment options for patients with chronic hepatitis delta.

Modified nucleoside triphosphates (dNTPs) are a versatile platform for the generation of high-density functionalized nucleic acids. The enzymatic polymerization of dNTPs allows the introduction of sensible functionalities that might not be compatible with the standard automated synthesis of oligonucleotides. Their application to in vitro selections, an elegant chemical approach to Darwinian evolution, delivers modified aptamers and catalytic nucleic acids with potentially enhanced properties. This review article highlights some recent synthetic examples of dNTPs bearing functionalities that are either found in the active site of protein enzymes or have been employed in organocatalysis and further underscores their usefulness in the development of some modified catalytic nucleic acids with special emphasis on M2+-independent RNA-cleaving DNAzymes.

Untersuchung zur Eignung renal ausgeschiedener modifizierter Nukleoside in der Frühdiagnostik und in der Verlaufskontrolle von nicht-kleinzelligen Bronchialkarzinomen

Nucleosides from natural sources play an increasingly important role as model compounds in pharmaceutical research against cancer, bacterial and viral infections as well as against fungal diseases. As part of the present work, the first total synthesis of the nucleosides 4'-epi-Trachycladine A and B was successfully accomplished. The natural nucleosides Trachycladine A and B were isolated for the first time in 1995 by T. F. Molinski and P. A. Searle from the marine sponge Trachycladus laevispirulifer (collected from Exmouth Gulf, Western Australia). The stereogenic centres of the sugar moiety of target compounds 4'-epi-Trachycladine A and B were created using SAMP hydrazone methodology. The total yield of the synthesis was 27% and 25% respectively over 13 synthetic steps. Glycosidases and glycosyltransferases play an important role in various metabolic processes. Iminosugars, which act as inhibitors of these enzymes, can therefore be used as agents in several therapeutic areas: as inhibitors of tumour metastases and viral replications, anti-diabetic agents and for the treatment of lysosomal storage diseases. Other iminosugars act as neuramidase inhibitors and are thus promising anti-influenza agents. The iminosugars Batzellasides A-C were isolated by N. L. Segraves and P. Crews from the marine sponge Batzella sp., collected from the west coast of Madagascar. Batzellaside A could be isolated in significantly larger amounts than Batzellaside B and Batzellaside C. All three compounds showed a moderate biological activity in the initial in vitro tests with Staphylococcus epidermidis. An attempt to develop a diastereo- and enantioselective synthetic route to naturally occurring azasugars Batzellasides A-C was performed. The key step in these syntheses was an organocatalytic Mannich reaction. Additionally, an attempt to develop an efficient synthetic approach to C-azanucleosides was undertaken. 2,2-Dimethyl-1,3-dioxan-5-on and a corresponding arylglyoxal were used as starting materials for these syntheses. As key step for the envisaged synthetic route, an organocatalytic aldol reaction would be used.

The new German and American guidelines on hepatitis B show similarities but also some discrepancies. In general, indication for therapy depends more on hepatitis B virus-(HBV-)DNA than alanine aminotransferase (ALT) values. Antivirals are recommended by German guidelines when HBV-DNA exceeds 10,000 copies/ml and ALT is increased more than twice the upper normal limit or when liver biopsy shows significant inflammation and fibrosis. By contrast, American guidelines recommend therapy only when HBV-DNA exceeds 100,000 copies/ml. American guidelines do not recommend lamivudine or telbivudine as initial monotherapy because of risk for resistance, but adefovir or entecavir. By contrast, according to German guidelines monotherapy with lamivudine, telbivudine, adefovir or entecavir may be initiated, if HBV-DNA is1 million copies/ml and cirrhosis is absent. Both guidelines recommend to monitor HBV-DNA even in the absence of therapy. Under antiviral therapy HBV-DNA should be measured more often than previously recommended to early identify lack of response and upcoming resistance. When resistance occurs, combination therapy is indicated. Risk for resistance is low as long as viral suppression is effective. In both guidelines liver biopsy should be considered when there are doubts on indication of therapy or selection of antiviral substances. In the presence of severe fibrosis and high HBV-DNA, antiviral substances should have high potency and low risk for resistance.

Therapeutic option for hepatitis B virus infection have significantly improved in recent years. Moreover, new insights in the natural history of hepatitis B required an update of current national guidelines. Therefore, the German network of competence on viral hepatitis (Hep-Net) has revised guidelines on diagnosis and treatment og HBV incetion in cooperation with the national societies for Gastroenterology, Pathology, Virology, and Pediatric Gastroenterology. Important alterations concern the indication for antiviral therapy considering an HBV viremia of 104 copies/ml (2000 IU/ml) as a critical level. Moreover, specific recommendations how to prevent and to treat antiviral drug resistance are given. Finally, the importance of HBV in the context of organ and bone marrow transplantation, treatment of coinfections and children and prophylaxis of HBV is covered.

In ruminants large amounts of nucleic acids associated with the microbial cell mass leaving the fore-stomach system via the abomasum enter the small intestine. In dairy cows this amounts to 100-200 g microbial nucleic acids per day. These nucleic acids are very efficiently digested in the small intestine whereby nucleosides were found to be the main degradation products. Therefore, this review centers mainly on the mechanisms of intestinal absorption of nucleosides and their role in nucleic acid digestion. Furthermore, metabolism of nucleosides in intestinal epithelial cells and its bearing for nucleoside absorption and salvage of nucleosides for nucleic acid synthesis in various tissues is considered. According to own studies using isolated intestinal brush-border membrane (BBM) vesicles (BBMV) from dairy cows purine and pyimidine nucleosides are transported actively by two separate Na+ co-transport systems (N1 and N2) across the bovine BBM, whereby transport activity in the small intestine decreases from proximal to distal. Guanosine and inosine appeared to be transported exclusively by N1 while thymidine and cytidine appeared to be transported exclusively by N2. Uridine and adenosine had an affinity to both transporters. In comparison to findings in man and rabbit, transport capacity (Vmax) of N1 and N2 in the BBM of cows was more than 10-fold higher. Similar findings were obtained in BBMV isolated from the small intestine of veal calves with rudimentary forestomach development in regard to nucleoside transport. Therefore, the high intestinal transport activity for nucleosides seems to be a genetically fixed property in the bovine, which is not related to a functional fore-stomach system.