SARS-CoV-2 RNA-dependent RNA polymerase in complex with cofactors in reduced condition

Gao, Yunrong; Yan, Liming; Huang, Youliang; Liu, F.; Cao, Lili; Wang, T.; Wang, Q.; Lou, Zhuangwei; Rao, Z.

doi:10.2210/pdb7btf/pdb

2020

DOI: 10.2210/pdb7btf/pdb

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SARS-CoV-2 RNA-dependent RNA polymerase in complex with cofactors in reduced condition

Yunrong Gao¹,

Liming Yan²,

Youliang Huang³

et al.

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Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Naseem-Khan

Berger

Leddin

et al. 2022

J. Chem. Inf. Model.

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Remdesivir was the first antiviral drug that received emergency use authorization from the United States Food and Drug Administration and is now formally approved to treat COVID-19. Remdesivir is a nucleotide analogue that targets the RNA-dependent RNA polymerase (RdRp) of coronaviruses, including SARS-CoV-2. The solution of multiple RdRp structures has been one of the main axes of research in the race against the SARS-CoV-2 virus. Several hypotheses of the mechanism of inhibition of RdRp by remdesivir have been proposed, although open questions remain. This work uses molecular dynamics simulations to explore the impact of remdesivir and two analogues as incoming nucleotides and of up to four incorporations of remdesivir along the primer strand on RdRp. The simulation results suggest that the overall structure and the dynamical behavior of RdRp are destabilized by remdesivir and the two analogues in the incoming position. The incorporation of remdesivir along the primer strand impacts specific non-bonded interactions between the nascent RNA and the polymerase subunit, as well as the overall dynamical networks on RdRp. The strongest impact on the structure and dynamics are observed after three incorporations, when remdesivir is located at position −A3, in agreement with previously reported experimental and computational results. Our results provide atomic-level details of the role played by remdesivir on the disruption of RNA synthesis by RdRp and the main drivers of these disruptions.

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Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Naseem-Khan

Berger

Leddin

et al. 2022

J. Chem. Inf. Model.

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Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?

et al. 2020

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Zn(II) is an inhibitor of SARS-CoV-2′s RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores–this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.

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SARS-CoV-2 RNA-dependent RNA polymerase in complex with cofactors in reduced condition

Cited by 2 publications

References 0 publications

Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?

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