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Nucleotide Analogues (nucleotide + analogue)
Selected AbstractsEfficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus-related hepatocellular carcinomaLIVER INTERNATIONAL, Issue 2 2009Ji Hoon Kim Abstract Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus-related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child,Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV-related HCC. [source] Discovery and recognition of purine receptor subtypes on plateletsDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Susanna M.O. HouraniArticle first published online: 9 MAY 200 Abstract The effects of purines on platelets have been known since the 1960s, when Born demonstrated aggregation induced by ADP and its inhibition by adenosine and by ATP. The inhibition by adenosine is not specific for ADP, and adenosine acts at a separate receptor to stimulate adenylate cyclase, which has an inhibitory effect on platelet function. Studies using selective agonists and antagonists have shown that the platelet receptor is of the A2A subtype and this has been confirmed using A2A knockout mice. The situation with ADP is more complex, and there has been controversy about the number of ADP receptors on platelets. ADP causes shape change, aggregation, mobilisation of calcium from intracellular stores, rapid calcium influx, and inhibition of adenylate cyclase, and the relationship between these is becoming clearer. Two cloned P2 receptors have been detected on platelets, P2X1 and P2Y1, and a third P2Y receptor is thought to exist. The P2X1 receptor is responsible for the rapid calcium influx and can be activated by ATP as well as by ADP, but is likely to be desensitised under normal experimental conditions and its pathophysiological role is uncertain. The P2Y1 receptor is responsible for calcium mobilisation, shape change, and the initiation of aggregation, and these responses are abolished in P2Y1 knockout mice, while the other P2Y receptor is responsible for inhibition of adenylate cyclase and is required for full aggregation. ATP is a competitive antagonist at both these P2Y receptors, while some nucleotide analogues can discriminate between them. Drug Dev. Res. 52:140,149, 2001. © 2001 Wiley-Liss, Inc. [source] Synthesis and Properties of New Nucleotide Analogues Possessing Squaramide Moieties as New Phosphate Isosters,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 24 2005Kohji Seio Abstract New analogues of 2,-deoxynucleotides and ribonucleotides incorporating a unique squaramide structure were synthesized. Because of the strong acidity of this moiety (pKa = 2.3), these nucleotide analogues exist in a monoanionic form, which can be regarded as an electronic isoster of 5,-nucleotides under physiological conditions. The synthesis of the nucleotide analogues was achieved through the condensation of 5,- or 3,-aminonucleosides with dimethyl squarate, whilst the selective removal of the methyl group was effectively accomplished by treatment with sodium bromide. In addition, we also synthesized 3,,5,-cyclic nucleotide analogues from the 3,,5,-diazidonucleoside derivatives. NMR analysis revealed that their ribose puckering was of an N-type form, identical to that in cAMP and cGMP. Because of the unique structural, electronic, and conformational properties of squaramide-type nucleotide analogues, these analogues should be quite interesting as potential biologically active compounds such as antiviral and anticancer agents. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Review article: success and failure of nucleoside and nucleotide analogues in chronic hepatitis BALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2007W. F. LEEMANS SUMMARY Background, Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments. Aim, To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues. Results, Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven. Conclusions, HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures. [source] Alanine scan mutagenesis of the switch I domain of the Caulobacter crescentus CgtA protein reveals critical amino acids required for in vivo functionMOLECULAR MICROBIOLOGY, Issue 4 2001B. Lin The Caulobacter crescentus CgtA protein is a member of the Obg/GTP1 subfamily of monomeric GTP-binding proteins. In vitro, CgtA displays moderate affinity for both GDP and GTP and displays rapid exchange rate constants for either nucleotide, indicating that the guanine nucleotide-binding and exchange properties of CgtA are different from those of the well-characterized Ras-like GTP-binding proteins. The Obg/GTP1 proteins share sequence similarity along the putative effector-binding domain. In this study, we examined the functional consequences of altering amino acid residues within this conserved domain, and identified that T193 was critical for CgtA function. The in vitro binding, exchange and GTP hydrolysis of the T192A, T193A and T192AT193A mutant proteins was examined using fluorescent guanine nucleotide analogues (mant-GDP and mant-GTP). Substitution of either T192 and/or T193 for alanine modestly reduced binding to GDP and significantly reduced the binding affinity for GTP. Furthermore, the T193A mutant protein was more severely impaired for binding GTP than the T192A mutant. The T193A mutation appeared to account solely for the impaired GTP binding of the T192AT193A double mutation. This is the first report that demonstrates that a confirmed defect in guanine nucleotide binding and GTP hydrolysis of an Obg-like protein results in the lack of function in vivo. [source] Structure of Ynk1 from the yeast Saccharomyces cerevisiaeACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2008Huabing Wang Nucleoside diphosphate kinase (NDPK) catalyzes the transfer of the ,-phosphate from nucleoside triphosphates to nucleoside diphosphates. In addition to biochemical studies, a number of crystal structures of NDPK from various organisms, including both native proteins and complexes with nucleotides or nucleotide analogues, have been determined. Here, the crystal structure of Ynk1, an NDPK from the yeast Saccharomyces cerevisiae, has been solved at 3.1,Å resolution. Structural analysis strongly supports the oligomerization state of this protein being hexameric rather than tetrameric. [source] Antiviral prodrugs , the development of successful prodrug strategies for antiviral chemotherapyBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006Erik De Clercq Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral ,prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date. British Journal of Pharmacology (2006) 147, 1,11. doi:10.1038/sj.bjp.0706446 [source] Polymerase-Catalysed Incorporation of Glucose Nucleotides into a DNA DuplexCHEMISTRY - A EUROPEAN JOURNAL, Issue 22 2009Marleen Renders Abstract Active but unselective: Nucleoside triphosphates possessing glucose moieties (such as those depicted) instead of the natural furanose rings are recognised by the active sites of polymerases. Polymerases therefore seem to be very unspecific in their recognition patterns. The enzymatic recognition of six-membered ring nucleoside triphosphates,in particular the 6,-triphosphates of (,- D -glucopyranosyl)thymine, (2,,3,-dideoxy-,- D -glucopyranosyl)thymine, (3,,4,-dideoxy-,- D -glucopyranosyl)thymine and (2,,3,-dideoxy-,- D -glucopyranosyl)adenine,was investigated. Despite the facts that the pyranose nucleic acids obtained by polymerisation of these monomers do not hybridise in solution with DNA and that the geometry of a DNA strand in a natural duplex differs from that of a pyranose nucleic acid, elongation of the DNA duplex with all four nucleotide analogues by Vent,(exo,) polymerase was observed. Modelling experiments showed that hydrogen bonds are formed when 2,,3,-dideoxy-,-homo-T building blocks or ,- D - gluco -T building blocks are incorporated opposite adenosine residues in the template but not when they are incorporated opposite thymine residues in the template. The model shows a near perfect alignment of a secondary hydroxy group at the end of the primer and the ,-phosphate group of the incoming triphosphate. The results of these experiments provide new information on the role of the active site of the enzyme in the polymerisation reaction. [source] Multidrug resistance-associated proteins and implications in drug developmentCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2010Ya-He Liu Summary 1.,The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood,brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2.,Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C4. Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3.,Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4.,Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5.,A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug,drug interactions, as well as help overcome drug resistance. [source] | |||||||||||||