ArticleAntimicrobial agents and chemotherapy2007
Pyrophosphorolytic excision of nonobligate chain terminators by hepatitis C virus NS5B polymerase.
Article in Antimicrobial agents and chemotherapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
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- NMPylation and de-NMPylation of SARS-CoV-2 nsp9 by the NiRAN domain.Nucleic acids research · 2021Article
- RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.European journal of medicinal chemistry · 2021Review
- 2'-C-methylated nucleotides terminate virus RNA synthesis by preventing active site closure of the viral RNA-dependent RNA polymerase.The Journal of biological chemistry · 2019Article
- The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold.Antiviral research · 2018Review
- Signatures of Nucleotide Analog Incorporation by an RNA-Dependent RNA Polymerase Revealed Using High-Throughput Magnetic Tweezers.Cell reports · 2017Article
- The uncoupling of catalysis and translocation in the viral RNA-dependent RNA polymerase.RNA biology · 2017Review
- Evaluation of Sofosbuvir (β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>.Scientific reports · 2017Article
- Mutagenic Effects of Ribavirin on Hepatitis E Virus-Viral Extinction versus Selection of Fitness-Enhancing Mutations.Viruses · 2016Review
- A Complex Network of Interactions between S282 and G283 of Hepatitis C Virus Nonstructural Protein 5B and the Template Strand Affects Susceptibility to Sofosbuvir and Ribavirin.Antimicrobial agents and chemotherapy · 2016Article
- Biochemical Evaluation of the Inhibition Properties of Favipiravir and 2'-C-Methyl-Cytidine Triphosphates against Human and Mouse Norovirus RNA Polymerases.Antimicrobial agents and chemotherapy · 2015Article
- Dynamics of hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B in complex with RNA.The Journal of biological chemistry · 2014Article
- Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1.Journal of virology · 2014Article
- Inhibition of hepatitis C viral RNA-dependent RNA polymerase by α-P-boranophosphate nucleotides: exploring a potential strategy for mechanism-based HCV drug design.Antiviral research · 2013Article
- HIV-1 reverse transcriptase and antiviral drug resistance. Part 2.Current opinion in virology · 2013Review
- NTP-mediated nucleotide excision activity of hepatitis C virus RNA-dependent RNA polymerase.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Assembly, purification, and pre-steady-state kinetic analysis of active RNA-dependent RNA polymerase elongation complex.The Journal of biological chemistry · 2012Article
- HIV-1 polymerase inhibition by nucleoside analogs: cellular- and kinetic parameters of efficacy, susceptibility and resistance selection.PLoS computational biology · 2012Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 (PP(i)), 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.
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