Safety, Pharmacokinetics, and Antiviral Activity of AT-527, a Novel Purine Nucleotide Prodrug, in Hepatitis C Virus-Infected Subjects with or without Cirrhosis

Berliba, Elina; Bogus, Maxim; Vanhoutte, Frédéric; Berghmans, Pieter Jan; Good, Steven S.; Moussa, Adel; Pietropaolo, Keith; Murphy, Robert L.; Zhou, Xuan; Sommadossi, Jean Pierre

doi:10.1128/aac.01201-19

Cited by 28 publications

(32 citation statements)

References 18 publications

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“…Since plasma levels of the nucleoside metabolite AT-273 arise from catabolism of its intracellular phosphorylated forms and the TP is the predominant form in all cells and tissues examined to date (8), plasma levels of AT-273 are considered a surrogate for intracellular levels of AT-9010. This hypothesis is supported by the observation that plasma AT-273 concentrations accurately reflect the antiviral activity of escalating doses of AT-527 in HCV-infected subjects (7). However, some tissues may contribute to this pool more than others.…”

Section: Downloaded Frommentioning

confidence: 83%

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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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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Section: Downloaded Frommentioning

confidence: 83%

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

117

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: 95%

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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“…Then, the monophosphate is transformed to guanosine analog by adenosine deaminase like protein 1 (ADALP1) and further phosphorylated by guanylate kinase 1 (GUK1) and nucleoside diphosphate kinase (NDPK) to the pharmacologically active form of AT-527 diphosphate (also reported as AT-9010) ( Figure S3 ) [ 78 ]. The safety, pharmacokinetics, and antiviral activity of AT-527 was earlier established in HCV-infected subjects with and without cirrhosis [ 79 ]. The drug is currently being evaluated in a phase 2 double-blind, randomized, placebo-controlled study to determine its efficacy and safety in patients with moderate COVID-19 symptoms (NCT04396106; n = 190).…”

Section: Viral Polymerase Inhibitorsmentioning

confidence: 99%

Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

Al‐Horani

Kar

2020

Viruses

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The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.

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Safety, Pharmacokinetics, and Antiviral Activity of AT-527, a Novel Purine Nucleotide Prodrug, in Hepatitis C Virus-Infected Subjects with or without Cirrhosis

Cited by 28 publications

References 18 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)

Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

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