AT-527 is a potent<i>in vitro</i>replication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic

Good, Steven S.; Westover, Jonna B.; Jung, Kie Hoon; Colla, Paolo La; Collu, Gabriella; Moussa, Adel; Canard, Bruno; Sommadossi, Jean‐Pierre

doi:10.1101/2020.08.11.242834

Cited by 13 publications

(14 citation statements)

References 14 publications

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“…After oral dosing, the predicted concentration of the active metabolite in pulmonary tissue suggests that AT-527 may be an effective treatment option for individuals infected with COVID-19. (The in vitro virus inhibition data was submitted to an online preprint archive (10). )…”

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confidence: 99%

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

Good

Westover

Jung

et al. 2021

Antimicrob Agents Chemother

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118

126

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The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in HCV-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 μM, very similar to its EC90 against HCoV-229E, HCoV-OC43 and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of non-human primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.

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confidence: 99%

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

Good

Westover

Jung

et al. 2021

Antimicrob Agents Chemother

Self Cite

118

126

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“…Since this article was written (January-February 2021) and peerreviewed, new potential antivirals for the treatment of COVID-19 were reported, such as: (1) AT-511, announced as the 'free base form' of AT-527 60 , but basically the same compound as described by Berliba et al 61 ; (2) PF-07304814 and PF-00835231 (SARS-CoV-2 3CL protease inhibitors) 62 ; and (3) ALG-09711 63 that would directly inhibit the SARS-CoV-2 3CL protease inhibitor and K777 64 that would indirectly do so (via inhibition of cathepsin L).…”

Section: Addendummentioning

confidence: 99%

Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19)

Clercq¹

2021

Microbiol. Aust.

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Compared with vaccines, antivirals for curbing COVID-19 (SARS-CoV-2 infection) have been developed at a much lower pace. Favipiravir has proven efficacious (in hamsters) but only at a very high dose which may not be feasible in humans. Remdesivir is the sole antiviral approved by the US FDA, but it has not been extensively evaluated for its safety.EIDD-1931 and EIDD-2801 have not been evaluated clinically. M pro (protease) inhibitors likewise need to be subjected to clinical efficacy and safety studies. Remdesivir is a C-nucleoside and this class of compounds should be further evaluated.Polyanionic substances interfering with virus adsorption to the host cells have not been explored. They may possibly be administered by inhalation. Corticosteroids (such as dexamethasone), while virus-stimulating rather than inhibitory, may counteract the 'cytokine storm'. Combination of (two or more of) the compounds mentioned above may offer an increased benefit through a synergistic interaction.

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“…Only 7% of clinical trials evaluating pharmacologic treatments for COVID-19 in the US are evaluating oral drugs with proposed antiviral mechanisms. Of the RCTs of outpatient oral treatment, 11 drugs have in vitro evidence of SARS-CoV-2 inhibition: AT-527, camostat mesylate, dipyridamole, ebselen, EIDD-2801, favipiravir, ivermectin, niclosamide, nitazoxanide, oleandrin, and toremifene (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). Of these drugs, only favipiravir has prior results from prospective clinical trials, which have had conflicting results (32,50,51).…”

Section: Current Clinical Trials Of Drugs For Covid-19 In the United mentioning

confidence: 99%

“…EIDD-2801, a ribonucleoside analog, inhibits 50% of SARS-CoV-2 replication in cell culture at concentrations <0.1 μM, was active against SARS-CoV, MERS and several bat coronavirus strains, and reduced lung viral loads and improved pulmonary function in a mouse model of SARS-CoV and MERS ( 40 ). AT-527, a guanosine nucleotide analog previously studied in patients with hepatitis C, inhibited 90% of SARS-CoV-2 replication at a concentrations close to 0.5 μM, and was active against SARS-CoV and human coronaviruses, HCoV-229E and HCoV-OC43 ( 47 ). While encouraging that a few drugs in clinical trials could be repurposed to treat COVID-19 and emerging coronaviruses, this small number reveals a large unmet need for preclinical coronavirus drug development.…”

Section: Current Clinical Trials Of Drugs For Covid-19 In the United mentioning

confidence: 99%

The Need for Antiviral Drugs for Pandemic Coronaviruses From a Global Health Perspective

et al. 2020

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Respiratory failure due to SARS-CoV-2 has caused widespread mortality, creating an urgent need for effective treatments and a long-term need for antivirals for future emergent coronaviruses. Pharmacotherapy for respiratory viruses has largely been unsuccessful with the exception of early treatment of influenza viruses, which shortens symptom duration and prevents infection in close contacts. Under the rapidly evolving circumstances of the COVID-19 pandemic, most clinical trials of experimental treatments in the United States have focused on later stages of the disease process. Worldwide, the clinical studies of the most impactful drugs, remdesivir and dexamethasone in ACTT-1, RECOVERY, and Solidarity, have studied hospitalized patients. Less than half of clinical trials in the U.S. have investigated oral agents, and the majority have taken place in hospitals at a disease stage where the viral load is already decreasing. The limited success of treatments for respiratory viruses and the viral dynamics of COVID-19 suggest that an antiviral therapy with the greatest impact against pandemic coronaviruses would be orally administered, well-tolerated, target a highly conserved viral protein or host-coronavirus interaction and could be used effectively throughout the world, including resource-poor settings. We examine the treatment of respiratory viral infections and current clinical trials for COVID-19 to provide a framework for effective antiviral therapy and prevention of future emergent coronaviruses and call attention to the need for continued preclinical drug discovery.

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AT-527 is a potentin vitroreplication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic

Cited by 13 publications

References 14 publications

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19)

The Need for Antiviral Drugs for Pandemic Coronaviruses From a Global Health Perspective

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