What Do We Know About Remdesivir Drug Interactions?

Yang, Katherine

doi:10.1111/cts.12815

Cited by 80 publications

(74 citation statements)

References 8 publications

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“…We also revealed that the chemical modification at the ribose of Remdesivir is responsible for the dual inhibitory function to terminate both nucleotide addition and proofreading. This knowledge is valuable for offering guiding principles to maintain the property of Remdesivir to inhibit viral replication, while optimizing Remdesivir's other drug properties such as preventing its breakdown in the liver (71) and reducing its cytotoxicity (26). Our work also provides a promising general strategy for designing prospective nucleotide analogue inhibitors to treat COVID-19.…”

Section: Resultsmentioning

confidence: 94%

Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication

Zhang

Yuan

et al. 2020

Preprint

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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) provides a promising but challenging drug target due to its intrinsic proofreading exoribonuclease (ExoN) function. Nucleoside triphosphate (NTP) analogues added to the growing RNA chain should supposedly terminate viral RNA replication, but ExoN can cleave the incorporated compounds and counteract their efficacy. 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 (MD) simulations with an accumulated simulation time of 12.6 microseconds to elucidate the molecular mechanisms underlying the inhibitory effects of remdesivir in nucleotide addition (RdRp complex: nsp12-nsp7-nsp8) and proofreading (ExoN complex: nsp14-nsp10). We found that the 1'-cyano group of remdesivir possesses the dual role of inhibiting both nucleotide addition and proofreading. For nucleotide addition, we showed that incorporation of one remdesivir is not sufficient to terminate RNA synthesis. Instead, the presence of the polar 1'-cyano group of remdesivir at an upstream site causes instability via its electrostatic interactions with a salt bridge formed by Asp865 and Lys593, rendering translocation unfavourable. This may eventually lead to a delayed chain termination of RNA extension by three nucleotides. For proofreading, remdesivir can inhibit cleavage via the steric clash between the 1'-cyano group and Asn104. To further examine the role of 1'-cyano group in remdesivir's inhibitory effects, we studied three additional NTP analogues with other types of modifications: favipiravir, vidarabine, and fludarabine. Our simulations suggest that all three of them are prone to ExoN cleavage. Our computational findings were further supported by an in vitro assay in Vero E6 cells using live SARS-CoV-2. The dose-response curves suggest that among tested NTP analogues, only remdesivir exerts significant inhibitory effects on viral replication. Our work provides plausible mechanisms at molecular level on how remdesivir inhibits viral RNA replication, and our findings may guide rational design for new treatments of COVID-19 targeting viral replication.

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Section: Resultsmentioning

confidence: 94%

Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication

Zhang

Yuan

et al. 2020

Preprint

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“…The scenario is constantly changing, so potential DDIs involving remdesivir, corticosteroids and anticoagulants should be considered. According to available literature, the risk of pharmacokinetic- and pharmacodynamic-based DDIs is low for remdesivir [ 40 , 41 ]. However, since this drug is a substrate of cytochromes 3A4, 2D6, and 2C8, the potential co-administration of inhibitors can lead to a potential increase in remdesivir levels.…”

Section: Discussionmentioning

confidence: 99%

Drug–Drug Interactions and Prescription Appropriateness in Patients with COVID-19: A Retrospective Analysis from a Reference Hospital in Northern Italy

et al. 2020

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Background Patients hospitalised with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2; coronavirus 2019 disease (COVID-19)] infection are frequently older with co-morbidities and receiving polypharmacy, all of which are known risk factors for drug–drug interactions (DDIs). The pharmacological burden may be further aggravated by the addition of treatments for COVID-19. Objective The aim of this study was to assess the risk of potential DDIs upon admission and during hospitalisation in patients with COVID-19 treated at our hospital. Methods We retrospectively analysed 502 patients with COVID-19 (mean age 61 ± 16 years, range 15–99) treated at our hospital with a proven diagnosis of SARS-CoV-2 infection hospitalised between 21 February and 30 April 2020 and treated with at least two drugs. Results Overall, 68% of our patients with COVID-19 were exposed to at least one potential DDI, and 55% were exposed to at least one potentially severe DDI. The proportion of patients experiencing potentially severe DDIs increased from 22% upon admission to 80% during hospitalisation. Furosemide, amiodarone and quetiapine were the main drivers of potentially severe DDIs upon admission, and hydroxychloroquine and particularly lopinavir/ritonavir were the main drivers during hospitalisation. The majority of potentially severe DDIs carried an increased risk of cardiotoxicity. No potentially severe DDIs were identified in relation to tocilizumab and remdesivir. Conclusions Among hospitalised patients with COVID-19, concomitant treatment with lopinavir/ritonavir and hydroxychloroquine led to a dramatic increase in the number of potentially severe DDIs. Given the high risk of cardiotoxicity and the scant and conflicting data concerning their efficacy in treating SARS-CoV-2 infection, the use of lopinavir/ritonavir and hydroxychloroquine in patients with COVID-19 with polypharmacy needs to be carefully considered.

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“…In vitro, remdesivir is a substrate for CYP2C8, 2D6 and 3A4, P-gp and OATP1B1, as well as esterases in tissue and plasma [18,35,37]. Strong inhibitors of the hydrolytic pathway or of CYP2C8, 2D6 or 3A4 may increase remdesivir exposure [18]; the use of strong inducers (e.g.…”

Section: Features and Properties Of Remdesivirmentioning

confidence: 99%

“…Dexamethasone, a moderate inducer of CYP3A and P-gp, is unlikely to have clinically significant interactions with remdesivir [18]. Remdesivir is an inhibitor of CYP3A4, OATP1B1 and OATP1B3 in vitro [18,35,37]. While no data are available, plasma concentrations of drugs that are CYP3A or OATP1B1/1B3 substrates may be transiently increased by remdesivir and it is thus suggested that CYP3A4 or OATP1B1/1B2 substrates should be administered ≥ 2 h after remdesivir [17,18].…”

Section: Features and Properties Of Remdesivirmentioning

confidence: 99%

Remdesivir: First Approval

Lamb

2020

Drugs

216

162

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The antiviral agent remdesivir (Veklury ® ; Gilead Sciences), nucleotide analogue prodrug, has broad-spectrum activity against viruses from several families. Having demonstrated potent antiviral activity against coronaviruses in preclinical studies, remdesivir emerged as a candidate drug for the treatment of the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, during the current global pandemic. Phase III evaluation of remdesivir in the treatment of COVID-19 commenced in early 2020 and has thus far yielded promising results. In late May 2020, Taiwan conditionally approved the use of remdesivir in patients with severe COVID-19. This was followed by a rapid succession of conditional approvals in various countries/regions including the EU and Canada. Preceding these conditional approvals, an emergency use authorization for remdesivir had been granted in the USA (on 1 May 2020) and a special approval for emergency use was granted in Japan (on 7 May 2020). This article summarizes the milestones in the development of remdesivir leading to its first conditional approval for the treatment of COVID-19. Remdesivir (Veklury®): Key points A nucleotide analogue prodrug is being developed by Gilead Sciences for the treatment of COVID-19

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What Do We Know About Remdesivir Drug Interactions?

Cited by 80 publications

References 8 publications

Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication

Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication

Drug–Drug Interactions and Prescription Appropriateness in Patients with COVID-19: A Retrospective Analysis from a Reference Hospital in Northern Italy

Remdesivir: First Approval

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