Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

Eastman, Richard T.; Roth, Jacob S.; Brimacombe, Kyle R.; Simeonov, Anton; Shen, Min; Patnaik, Samarjit; Hall, Matthew D.

doi:10.1021/acscentsci.0c00489

Cited by 819 publications

(831 citation statements)

References 90 publications

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“…RDV is a prodrug designed to bypass the first phosphorylation of the Remdesivir nucleoside (RVn) which may be rate limiting in the synthesis of RVn-triphosphate, the active metabolite. 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: 79%

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: 79%

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

Schooley

Carlin

Beadle

et al. 2020

Preprint

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“…Remdesivir (RDV), a nucleotide analogue targeting the SARS-CoV-2 RdRp, is currently used for the treatment of COVID-19 under FDA emergency authorization. 27 The active triphosphate form of Remdesivir possesses a ribose with an OH group at both the 2' and 3' positions, while Sofosbuvir triphosphate has a 2'-F,Me-deoxyribose. The chemical stability of deoxyribose is much higher than that of the ribose.…”

Section: Introductionmentioning

confidence: 99%

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

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“…Remdesivir has broad-spectrum antiviral activity against SARS-CoV, SARS-CoV-2, and MERS-CoV in cell culture. [3][4][5] The antiviral efficacy was further confirmed in MERS-CoV infection mouse and rhesus macaque models. 6,7 Additional RdRp inhibitors under investigation for SARS-CoV-2 include EIDD-2801, favipiravir (T-705), ribavirin, and galidesivir.…”

Section: Introductionmentioning

confidence: 83%

Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M^proand cathepsin L

Sacco

Lagarias

et al. 2020

Preprint

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The main protease (Mpro) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently discovered several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of Mpro in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent Mpro inhibitors in vitro. The structure of Mpro with calpain inhibitor II confirmed the S1 pocket of Mpro can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1’ pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1’ pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of three GC-376 analogues UAWJ246, UAWJ247, and UAWJ248 provide insight to the sidechain preference of the S1’, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the α-ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of Mpro inhibitors as SARS-CoV-2 antivirals.

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Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

Cited by 819 publications

References 90 publications

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

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

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M^proand cathepsin L

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Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

Cited by 819 publications

References 90 publications

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

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

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against Mproand cathepsin L

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Product

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About

Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M^proand cathepsin L