Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice

Pruijssers, Andrea J.; George, Amelia S.; Schäfer, Alexandra; Leist, Sarah R.; Gralinksi, Lisa E.; Dinnon, Kenneth H.; Yount, Boyd; Agostini, Marco; Stevens, Laura J.; Chappell, James D.; Lu, Xiaotao; Hughes, Tia M.; Gully, Kendra L.; Martinez, David R.; Brown, Ariane J.; Graham, Rachel L.; Perry, Jason K.; Pont, Venice Du; Pitts, Jared; Ma, Bin; Babusis, Darius; Murakami, Eisuke; Feng, Joy Y.; Bilello, John P.; Porter, Danielle; Cihlář, Tomáš; Baric, Ralph S.; Denison, Mark R.; Sheahan, Timothy P.

doi:10.1016/j.celrep.2020.107940

Cited by 432 publications

(586 citation statements)

References 58 publications

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“…This occurs by the successive action of carboxyesterases, cathepsin A and phosphoramidases [16,23]. However, this approach does not appear to provide any benefit in Vero E6 cells, a monkey kidney cell line, as shown by Pruijssers et al [24] and by our results showing the antiviral activity of RVn is greater than that of RDV.…”

Section: Discussionmentioning

confidence: 78%

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs

Schooley

Carlin

Beadle

et al. 2020

Preprint

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The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells

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Section: Discussionmentioning

confidence: 78%

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs

Schooley

Carlin

Beadle

et al. 2020

Preprint

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“…Next, compounds were tested in Vero cells infected with SARS‐CoV‐2 at a multiplicity‐of‐infection (MOI) of 0.1 (Fig A), resulting in death of ~ 50% of the cell population. Remdesivir (RDV) (preprint: Pruijssers et al , ; Wang et al , ), the only available drug approved for treatment of COVID‐19, was used at 12.5 μM concentration (Choy et al , ), leading to a ~ 90% reversal of the SARS‐CoV‐2 induced CPE. Hydroxychloroquine (HCQ), at 10 μM (Yao et al , ), rescued CPE also by ~ 90% (Figs B, and EV6C and D).…”

Section: Resultsmentioning

confidence: 99%

Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2

et al. 2020

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The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, noncovalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

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“…Indeed, we found that SARS-CoV-2 replication could be inhibited by SFV at high concentration, not only in hepatoma cells – but also in Calu-3 type II pneumocytes. Interestingly, RDV, which shares structural characteristics with SFV, such as to be converted from the ProTide/prodrug to active metabolite, is active in the respiratory tract[39]. Moreover, there is a body of evidence suggesting that the ProTide phospharamidate protections would be dispensable from RDV in respiratory cells because the nucleoside analog, GS-441524, is active against human and feline CoV [39–41].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, RDV, which shares structural characteristics with SFV, such as to be converted from the ProTide/prodrug to active metabolite, is active in the respiratory tract[39]. Moreover, there is a body of evidence suggesting that the ProTide phospharamidate protections would be dispensable from RDV in respiratory cells because the nucleoside analog, GS-441524, is active against human and feline CoV [39–41]. Since there are open questions on the efficiency in which respiratory cells convert nucleosides to nucleotides, the nucleoside version of SFV (GS-331007) was tested against SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

Sacramento

Fintelman-Rodrigues

Temerozo

et al. 2020

Preprint

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The infection by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes major public health concern and economic burden. Although clinically approved drugs have been repurposed to treat individuals with 2019 Coronavirus disease (COVID-19), the lack of safety studies and limited efficiency as well jeopardize clinical benefits. Daclatasvir and sofosbuvir (SFV) are clinically approved direct-acting antivirals (DAA) against hepatitis C virus (HCV), with satisfactory safety profile. In the HCV replicative cycle, daclatasvir and SFV target the viral enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV and SARS-CoV-2 motivated us to further study the activity of daclatasvir and SFV against the new coronavirus. Daclatasvir consistently inhibited the production of infectious SARS-CoV-2 virus particles in Vero cells, in the hepatoma cell line HuH-7 and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 μM, respectively. Daclatasvir targeted early events during SARS-CoV-2 replication cycle and prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection. Sofosbuvir, although inactive in Vero cells, displayed EC50 values of 6.2 and 9.5 μM in HuH-7 and Calu-3 cells, respectively. Our data point to additional antiviral candidates, in especial daclatasvir, among drugs overlooked for COVID-19, that could immediately enter clinical trials.

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Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice

Cited by 432 publications

References 58 publications

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs

Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2

The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

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