Remdesivir—Bringing Hope for COVID-19 Treatment
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Abstract:
At the beginning of 2020, the world was swept with a wave of a new coronavirus disease, named COVID-19 by the World Health Organization (WHO 2). The causative agent of this infection is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data available on one of the promising therapeutic agents—nucleotide analog remdesivir (Gilead Sciences number GS-5734)—were evaluated. These data were concerned with remdesivir activation from the prodrug to the active molecule—triphosphate containing 1′-cyano group and modified nucleobase. This triphosphate competes with the natural substrate adenosine triphosphate. Additionally, its mechanisms of action based on RNA and proofreading exonuclease inhibition, leading to the delayed RNA chain termination of infected cells, and basic pharmacological data were assessed. Additionally, the analytical determination of remdesivir and its metabolites in cells and body liquids and also some data from remdesivir use in other RNA infections—such as Ebola, Nipah virus infection, and Middle East Respiratory Syndrome (MERS)—were summarized. More recent and more detailed data on the clinical use of remdesivir in COVID-19 were reported, showing the intensive efforts of clinicians and scientists to develop a cure for this new disease. Remdesivir as such represents one of the more promising alternatives for COVID-19 therapy, however the current understanding of this disease and the possible ways of dealing with it requires further investigation.Keywords:
Proofreading
Coronavirus
Adenosine triphosphate
Nucleoside triphosphate
Proofreading
Klenow fragment
RecBCD
DNA polymerase II
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Proofreading
Processivity
Primer (cosmetics)
Klenow fragment
DNA clamp
DNA polymerase I
DNA polymerase II
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Proofreading
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Proofreading
Klenow fragment
DNA polymerase I
RecBCD
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Proofreading
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Proofreading
Klenow fragment
DNA polymerase II
DNA clamp
Primer (cosmetics)
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The fidelity of DNA replication by DNA polymerase (DNAP) has long been an important issue in basic researches and application studies in biology. While numerous experiments have revealed details of the molecular structure and working mechanism of DNAP, theoretical studies of the fidelity issue are still lacking. Kinetic models which considered explicitly both the polymerase pathway and the exonuclease (proofreading) pathway were proposed since 1970s', but so far there was no rigorous treatment of such models. In this paper, we propose a new kinetic model of the exonuclease proofreading mechanism, based on some recent experimental observations. We present a rigorous analytical treatment of the steady-state kinetic equations including higher-order terminal effects, and then apply the results to the fidelity problem of some real DNAPs. Our results show good agreements with previous intuitive estimate of some DNAPs' fidelity under bio-relevant conditions.
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Kinetic theory and thermodynamics are applied to DNA polymerases with exonuclease activity, taking into account the dependence of the rates on the previously incorportated nucleotide. The replication fidelity is shown to increase significantly thanks to this dependence at the basis of the mechanism of exonuclease proofreading. In particular, this dependence can provide up to a hundred-fold lowering of the error probability under physiological conditions. Theory is compared with numerical simulations for the DNA polymerases of T7 viruses and human mitochondria.
Proofreading
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Proofreading
Primer (cosmetics)
Klenow fragment
Exonuclease III
DNA polymerase II
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