Remdesivir is a delayed translocation inhibitor of SARS CoV-2 replication in vitro
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Abstract
Remdesivir is a nucleoside analog approved by the FDA for treatment of COVID-19. Here, we present a 3.9-Å-resolution cryoEM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase complex, revealing full incorporation of three copies of remdesivir monophosphate (RMP) and a partially incorporated fourth RMP in the active site. The structure reveals that RMP blocks RNA translocation after incorporation of three bases following RMP, resulting in delayed chain termination, which can guide the rational design of improved antiviral drugs.
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SciScore for 10.1101/2020.12.14.422718: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Peaks were integrated with GeneMapper 5 software (ThermoFisher). GeneMappersuggested: (GeneMapper , RRID:SCR_014290)Images were recorded with SerialEM (Mastronarde, 2005), with a pixel size of 1.1Å over a defocus range of −1.5 to −2.5 μm. SerialEMsuggested: (SerialEM, RRID:SCR_017293)CTF correction, motion correction and particle picking were performed in real-time using WARP, resulting in 2,340,544 particles, which were uploaded to cryoSPARC v2 (Punjani et al., 2017). WARPsuggested…SciScore for 10.1101/2020.12.14.422718: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Peaks were integrated with GeneMapper 5 software (ThermoFisher). GeneMappersuggested: (GeneMapper , RRID:SCR_014290)Images were recorded with SerialEM (Mastronarde, 2005), with a pixel size of 1.1Å over a defocus range of −1.5 to −2.5 μm. SerialEMsuggested: (SerialEM, RRID:SCR_017293)CTF correction, motion correction and particle picking were performed in real-time using WARP, resulting in 2,340,544 particles, which were uploaded to cryoSPARC v2 (Punjani et al., 2017). WARPsuggested: (Warp, RRID:SCR_018071)Particles were subjected to multiple rounds of 3D classification in cryoSPARC, and a final set of 116,748 particles was refined to a global resolution of 3.89 Å based on the 0.143 FSC criterion. cryoSPARCsuggested: (cryoSPARC, RRID:SCR_016501)Non-proteinaceous molecules (i.e. RNA, ligands) were removed, and the template:primer duplex was built de novo in Coot (Emsley and Cowtan, 2004). Cootsuggested: (Coot, RRID:SCR_014222)Restraints for RMP were generated using eLBOW (Moriarty et al., 2009)), and structures were subjected to real-space refinement using Phenix (which resulted in a map-to-model FSC of 4.0Å at the 0.5 threshold) (Afonine et al., 2018). Phenixsuggested: (Phenix, RRID:SCR_014224)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 12. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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