Comprehensive Summary Supporting Clinical Investigation of GS-441524 for Covid-19 Treatment

Yan, Victoria C.; Müller, Florian

doi:10.31219/osf.io/mnhxu

Cited by 10 publications

(28 citation statements)

References 43 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: 75%

“…Other perceived disadvantages of RDV include a lack of oral bioavailability, a difficult synthesis, instability in plasma, inadequate delivery to lung and hepatotoxicity. [14,16] In patients with Covid-19 and in the Syrian hamster model of SARS-CoV-2 disease, in addition to high viral loads in nasal turbinate, trachea and lung, many other tissues are infected with SARS-CoV-2 as the infection proceeds including intestine, heart, liver, spleen, kidney, brain, lymph nodes and vascular endothelium. [25–29] However, RDV antiviral activity appears to vary widely in lung and kidney cell lines with EC 50 values of 1.65 μM in Vero E6 cells, 0.28 μM in Calu3 2B4, 0.010 μM in human alveolar epithelial cells (HAE), a 165-fold difference.…”

Section: Discussionmentioning

confidence: 99%

“…[24] It has been suggested that this may be due to variable amounts of the enzymes which convert RDV to RVn. [14,16] It will be important to evaluate the antiviral activity of RDV, RVn and these 3 novel lipid prodrugs of RVn in cells representing various tissues which are infected by SARS-CoV-2 and must be treated successfully if the infection is to be cleared.…”

Section: Discussionmentioning

confidence: 99%

“…It would be useful to have a highly active, orally bioavailable analog of RVn which provides sustained levels of intact antiviral drug in plasma since RDV persistence in plasma is known to be very short, 20 to 30 minutes. [16]…”

Section: Introductionmentioning

confidence: 99%

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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: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Schooley

Carlin

Beadle

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Gilead Science (GS)-441524 ( 11 , Figure 3 ) is a 1′-cyano adenosine analog, which is the main plasma metabolite of the more famous antiviral drug remdesivir (GS-5734, Figure 4 ) [ 130 ]. Several cellular studies conducted on 11 indicated an anti-SARS-CoV-2 activity comparable when not higher than remdesivir [ 131 ], with some studies pointing out that 11 would be even more convenient than remdesivir for the COVID-19 therapy [ 131 ]. GS-441524 advantages over remdesivir include ease of synthetic preparation, lower hepatic toxicity, as well as oral administration route (not suitable for remdesivir due to its poor liver stability) [ 131 ].…”

Section: Nucleoside Analogs As Anti-hcov Drugsmentioning

confidence: 99%

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

et al. 2021

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Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.

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The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations

Joyce

Hu²,

Wang³

2022

Med Chem Res

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The rapid development of effective vaccines to combat the SARS-CoV-2 virus has been an effective counter measure to decrease hospitalization and the mortality rate in many countries. However, with the risk of mutated strains decreasing the efficacy of the vaccine, there has been an increasing demand for antivirals to treat COVID-19. While antivirals, such as remdesivir, have had some success treating COVID-19 patients in hospital settings, there is a need for orally bioavailable, cost-effective antivirals that can be administered in outpatient settings to minimize COVID-19-related hospitalizations and death. Nirmatrelvir (PF-07321332) is an orally bioavailable M pro (also called 3CL pro ) inhibitor developed by Pfizer. It is administered in combination with ritonavir, a potent CYP3A4 inhibitor that decreases the metabolism of nirmatrelvir. This review seeks to outline the history of the rational design, the target selectivity, synthesis, drug resistance, and future perspectives of nirmatrelvir. Graphical abstract

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Comprehensive Summary Supporting Clinical Investigation of GS-441524 for Covid-19 Treatment

Abstract: Ongoing compilation of data supporting clinical advancement of GS-441524, the parent nucleoside of remdesivir, for the treatment of Covid-19. Last updated: Aug. 4, 2020.

Cited by 10 publications

References 43 publications

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

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

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations

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