scholarly journals Synthesis, andin vitroEnzymatic and Antiviral Evaluation of d4T Polyphosphate Derivatives as Chain Terminators

2012 ◽  
Vol 9 (10) ◽  
pp. 2186-2194 ◽  
Author(s):  
Shiqiong Yang ◽  
Christophe Pannecouque ◽  
Piet Herdewijn
Keyword(s):  
Chain Terminators

scholarly journals Primer-independent RNA sequencing with bacteriophage φ6 RNA polymerase and chain terminators

RNA ◽  
2001 ◽  
Vol 7 (5) ◽  
pp. 774-781 ◽  
Author(s):  
EUGENE V. MAKEYEV ◽  
DENNIS H. BAMFORD
Keyword(s):  
Rna Polymerase ◽  
Rna Sequencing ◽  
Chain Terminators

3?-Amino-Modified Nucleotides Useful as Potent Chain Terminators for current DNA sequencing methods

1994 ◽  
Vol 77 (2) ◽  
pp. 586-596 ◽  
Author(s):  
Mathias K. Herrlein ◽  
Renate E. Konrad ◽  
Joachim W. Engels ◽  
Torsten Holietz ◽  
Dieter Cech
Keyword(s):  
Dna Sequencing ◽  
Modified Nucleotides ◽  
Chain Terminators

Synthesis of UDP-glucose derivatives modified at the 3-OH as potential chain terminators of β-glucan biosynthesis

2008 ◽  
Vol 343 (6) ◽  
pp. 1012-1022 ◽  
Author(s):  
Ramona Danac ◽  
Lucy Ball ◽  
Sarah J. Gurr ◽  
Antony J. Fairbanks
Keyword(s):  
Glucose Derivatives ◽  
Chain Terminators

Synthetic Chain Terminators Off-Load Intermediates from a Type I Polyketide Synthase

ChemBioChem ◽  
2010 ◽  
Vol 11 (4) ◽  
pp. 539-546 ◽  
Author(s):  
Manuela Tosin ◽  
Lorena Betancor ◽  
Elaine Stephens ◽  
W. M. Ariel Li ◽  
Jonathan B. Spencer ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Type I ◽  
Chain Terminators

scholarly journals Pyrophosphorolytic Excision of Nonobligate Chain Terminators by Hepatitis C Virus NS5B Polymerase

2007 ◽  
Vol 51 (8) ◽  
pp. 2920-2928 ◽  
Author(s):  
Jérôme Deval ◽  
Megan H. Powdrill ◽  
Claudia M. D'Abramo ◽  
Luciano Cellai ◽  
Matthias Götte
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Synthesis ◽  
Hydroxyl Group ◽  
Rna Dependent Rna Polymerase ◽  
Dead End ◽  
Natural Counterpart ◽  
Ns5b Polymerase ◽  
Classical Chain ◽  
Chain Terminators

ABSTRACT Nonobligate chain terminators, such as 2′-C-methylated nucleotides, block RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). Previous studies with related viral polymerases have shown that classical chain terminators lacking the 3′-hydroxyl group can be excised in the presence of pyrophosphate (PPi), which is detrimental to the inhibitory activity of these compounds. Here we demonstrate that the HCV RdRp enzyme is capable of removing both obligate and clinically relevant nonobligate chain terminators. Pyrimidines are more efficiently excised than are purines. The presence of the next complementary templated nucleotide literally blocks the excision of obligate chain terminators through the formation of a dead-end complex (DEC). However, 2′-C-methylated CMP is still cleaved efficiently under these conditions. These findings show that a 2′-methylated primer terminus impedes nucleotide binding. The S282T mutation, associated with resistance to 2′-C-methylated nucleotides, does not affect the excision patterns. Thus, the decreased susceptibility to 2′-C-methylated nucleotides appears to be based solely on improved discrimination between the inhibitor and its natural counterpart. In conclusion, our data suggest that the phosphorolytic excision of nonobligate, pyrimidine-based chain terminators can diminish their potency. The templated nucleotide does not appear to provide protection from excision through DEC formation.

scholarly journals HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions

2012 ◽  
Vol 2012 ◽  
pp. 1-23 ◽  
Author(s):  
Francesca Esposito ◽  
Angela Corona ◽  
Enzo Tramontano
Keyword(s):  
Reverse Transcriptase ◽  
Drug Target ◽  
Polymerase Activity ◽  
Rnase H ◽  
Primary Target ◽  
Lethal Mutagenesis ◽  
Rt Inhibitors ◽  
Process Characteristic ◽  
Hiv 1 ◽  
Chain Terminators

During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT) protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs) that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.

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