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Phosphorothioate Di- and Trinucleotides as a Novel Class of Anti-Hepatitis B Virus Agents. Radhakrishnan P. Iyer, 2004.Several nucleoside analogs are under clinical development for use against hepatitis B virus (HBV) . Lamivudine (3TC), a nucleoside analog, and adefovir dipivoxil (ADV), an acyclonucleotide analog, are clinically approved . However, long-term treatment can induce viral resistance, and following the cessation of therapy, viral rebound is frequently observed . There continues to be a need for new antiviral agents with novel mechanisms of action . A library of more than 600 di- and trinucleotide compounds synthesized by parallel synthesis using a combinatorial strategy was screened for potential inhibitors of HBV replication using the chronically HBV-producing cell line 2.2.15 . Through an iterative process of synthesis, lead optimization, and screening, three analogs were identified as potent inhibitors of HBV replication: dinucleotides ORI-7246 (drug concentration at which a 10-fold reduction of HBV DNA was observed [EC90], 1.4 µM) and ORI-9020 (EC90, 1.2 µM) and trinucleotide ORI-7170 (EC90, 7.2 µM) . These analogs inhibited the replication of both strands of HBV DNA . No suppression of HBV protein synthesis or intracellular core particle formation by these analogs was observed . No inhibition of HBV DNA strand elongation by the analogs or their 5'-triphosphate versions was apparent in in vitro polymerase assays . Although the exact mechanism of action is not yet identified, present data are consistent with an inhibition of the HBV reverse transcriptase-directed priming step prior to elongation of the first viral DNA strand . In transient-transfection assays, these analogs inhibited the replication of 3TC-resistant HBV . Synergistic interactions in combination treatments between the analogs and either 3TC or ADV were observed . These compounds represent a novel class of anti-HBV molecules and warrant further investigation as potential therapeutic agents . Just Toothpicks and Logic: How Some Labs Succeed at Solving Complex Problems. Howard A. Shuman, 2003. OmcB, a c-Type Polyheme Cytochrome, Involved in Fe(III) Reduction in Geobacter sulfurreducens. Ching Leang, 2003.Microorganisms in the family Geobacteraceae are the predominant Fe(III)-reducing microorganisms in a variety of subsurface environments in which Fe(III) reduction is an important process, but little is known about the mechanisms for electron transport to Fe(III) in these organisms . The Geobacter sulfurreducens genome was found to contain a 10-kb chromosomal duplication consisting of two tandem three-gene clusters . The last genes of the two clusters, designated omcB and omcC, encode putative outer membrane polyheme c-type cytochromes which are 79% identical . The role of the omcB and omcC genes in Fe(III) reduction in G . sulfurreducens was investigated . OmcB and OmcC were both expressed during growth with acetate as the electron donor and either fumarate or Fe(III) as the electron acceptor . OmcB was ca . twofold more abundant under both conditions . Disrupting omcB or omcC by gene replacement had no impact on growth with fumarate . However, the OmcB-deficient mutant was greatly impaired in its ability to reduce Fe(III) both in cell suspensions and under growth conditions . In contrast, the ability of the OmcC-deficient mutant to reduce Fe(III) was similar to that of the wild type . When omcB was reintroduced into the OmcB-deficient mutant, the capacity for Fe(III) reduction was restored in proportion to the level of OmcB production . These results indicate that OmcB, but not OmcC, has a major role in electron transport to Fe(III) and suggest that electron transport to the outer membrane is an important feature in Fe(III) reduction in this organism .
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