Lack of antiviral activity of probenecid <i>in vitro</i> and in Syrian golden hamsters

Box, Helen J; Sharp, Joanne P.; Pennington, Shaun H.; Kijak, Edyta; Tatham, Lee M; Caygill, Claire H; Lopeman, Rose C.; Jeffreys, Laura N.; Herriott, Joanne; Neary, Megan; Valentijn, Anthony; Pertinez, Henry; Curley, Paul J.; Arshad, Usman; Rajoli, Rajith K R; Jochmans, Dirk; Vangeel, Laura; Neyts, Johan; Chatelain, Eric; Escudie, Fanny; Scandale, Ivan; Rannard, Steve; Stewart, James P.; Biagini, Giancarlo A.; Owen, Andrew

doi:10.1093/jac/dkad362

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Lack of antiviral activity of probenecid in vitro and in Syrian golden hamsters

research-article

Author(s): Helen J Box , Joanne Sharp , Shaun H Pennington , Edyta Kijak , Lee Tatham , Claire H Caygill , Rose C Lopeman , Laura N Jeffreys , Joanne Herriott , Megan Neary , Anthony Valentijn , Henry Pertinez , Paul Curley , Usman Arshad , Rajith K R Rajoli , Dirk Jochmans , Laura Vangeel , Johan Neyts , Eric Chatelain , Fanny Escudié , Ivan Scandale , Steve Rannard , James P Stewart , Giancarlo A Biagini , Andrew Owen

Publication date (Electronic): 23 November 2023

Journal: Journal of Antimicrobial Chemotherapy

Publisher: Oxford University Press

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Abstract

Objectives

Antiviral interventions are required to complement vaccination programmes and reduce the global burden of COVID-19. Prior to initiation of large-scale clinical trials, robust preclinical data to support candidate plausibility are required. This work sought to further investigate the putative antiviral activity of probenecid against SARS-CoV-2.

Methods

Vero E6 cells were preincubated with probenecid, or control media for 2 h before infection (SARS-CoV-2/Human/Liverpool/REMRQ0001/2020). Probenecid or control media was reapplied, plates reincubated and cytopathic activity quantified by spectrophotometry after 48 h. In vitro human airway epithelial cell (HAEC) assays were performed for probenecid against SARS-CoV-2-VoC-B.1.1.7 (hCoV-19/Belgium/rega-12211513/2020; EPI_ISL_791333, 2020-12-21) using an optimized cell model for antiviral testing. Syrian golden hamsters were intranasally inoculated (SARS-CoV-2 Delta B.1.617.2) 24 h prior to treatment with probenecid or vehicle for four twice-daily doses.

Results

No observable antiviral activity for probenecid was evident in Vero E6 or HAEC assays. No reduction in total or subgenomic RNA was observed in terminal lung samples ( P > 0.05) from hamsters. Body weight of uninfected hamsters remained stable whereas both probenecid- and vehicle-treated infected hamsters lost body weight ( P > 0.5).

Conclusions

These data do not support probenecid as a SARS-CoV-2 antiviral drug.

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Most cited references 27

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Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay Tomashek, Lori Dodd … (2022)

Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research

Nathalie Percie Du Sert, Viki Hurst, Amrita Ahluwalia … (2021)

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

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Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Angélica Jayk Bernal, Monica M. Gomes da Silva, Dany Musungaie … (2021)

Abstract Background New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Conclusions Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)

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Author and article information

Contributors

Helen J Box

Joanne Sharp

Shaun H Pennington:

ORCID: https://orcid.org/0000-0002-7160-6275

Edyta Kijak

Lee Tatham

Claire H Caygill

Rose C Lopeman

Laura N Jeffreys

Joanne Herriott

Megan Neary:

ORCID: https://orcid.org/0000-0002-4960-2139

Anthony Valentijn

Henry Pertinez

Paul Curley

Usman Arshad

Rajith K R Rajoli:

ORCID: https://orcid.org/0000-0002-6015-5712

Dirk Jochmans

Laura Vangeel

Johan Neyts

Eric Chatelain

Fanny Escudié:

ORCID: https://orcid.org/0000-0002-9177-9755

Ivan Scandale

Steve Rannard

James P Stewart

Giancarlo A Biagini

Andrew Owen:

ORCID: https://orcid.org/0000-0002-9819-7651

Journal

Journal ID (nlm-ta): J Antimicrob Chemother

Journal ID (iso-abbrev): J Antimicrob Chemother

Journal ID (publisher-id): jac

Title: Journal of Antimicrobial Chemotherapy

Publisher: Oxford University Press (US )

ISSN (Print): 0305-7453

ISSN (Electronic): 1460-2091

Publication date Collection: January 2024

Publication date (Electronic): 23 November 2023

Publication date PMC-release: 23 November 2023

Volume: 79

Issue: 1

Pages: 172-178

Affiliations

Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool , Liverpool L7 3NY, UK