Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication
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Abstract
COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising but challenging drug target due to its intrinsic proofreading exoribonuclease (ExoN). Remdesivir targeting SARS-CoV-2 RdRp exerts high drug efficacy in vitro and in vivo . However, its underlying inhibitory mechanisms remain elusive. Here, we performed all-atom molecular dynamics simulations with an accumulated simulation time of 24 microseconds to elucidate the molecular mechanisms underlying the inhibitory effects of Remdesivir. We found that Remdesivir’s 1’-cyano group of possesses the dual role of inhibiting nucleotide addition and proofreading. The presence of its polar 1’-cyano group at an upstream site in RdRp causes instability and hampers RdRp translocation. This leads to a delayed chain termination of RNA extension, which may also subsequently reduce the likelihood for Remdesivir to be cleaved by ExoN acting on the 3’-terminal nucleotide. In addition, our simulations suggest that Remdesivir’s 1’-cyano group can also disrupt the cleavage active site of ExoN via steric interactions, leading to a further reduced cleavage efficiency. Our work provides plausible molecular mechanisms on how Remdesivir inhibits viral RNA replication and may guide rational design for new treatments of COVID-19 targeting viral replication.
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SciScore for 10.1101/2020.04.27.063859: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources To consolidate the above-mentioned simulation results, we performed in vitro experiments in Vero E6 cells and show that NTP analogues favipiravir, vidarabine and fludarabine indeed fail to inhibit SARS-CoV-2 replication (Fig. 6F). Vero E6suggested: NoneSoftware and Algorithms Sentences Resources All simulations were performed with Gromacs 5.064. Gromacssuggested: (GROMACS, SCR_014565)Results from Barzooka: We also found bar graphs of continuous data. We …
SciScore for 10.1101/2020.04.27.063859: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources To consolidate the above-mentioned simulation results, we performed in vitro experiments in Vero E6 cells and show that NTP analogues favipiravir, vidarabine and fludarabine indeed fail to inhibit SARS-CoV-2 replication (Fig. 6F). Vero E6suggested: NoneSoftware and Algorithms Sentences Resources All simulations were performed with Gromacs 5.064. Gromacssuggested: (GROMACS, SCR_014565)Results from Barzooka: We also found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).
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