Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets

Cox, Robert; Wolf, Josef D.; Plemper, Richard K.

doi:10.1038/s41564-020-00835-2

Cited by 368 publications

(376 citation statements)

References 31 publications

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“…Ferrets are presumed to have been domesticated for more than two thousand years and have become more popular as pets in recent decades. This species is also widely used as a small animal model in the study of some human viral infections, such as influenza A virus and SARS coronavirus [ 1 , 4 ]. Laboratory studies also showed that cats and ferrets are highly susceptible to SARS-CoV-2 isolated from humans [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Seroprevalence in Household Domestic Ferrets (Mustela putorius furo)

Giner

Villanueva‐Saz

Tobajas

et al. 2021

Animals

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Animal infections with SARS-CoV-2 have been reported in different countries and several animal species have been proven to be susceptible to infection with SARS-CoV-2 both naturally and by experimental infection. Moreover, infections under natural conditions in more than 20 mink farms have been reported where humans could have been the source of infection for minks. However, little information is available about the susceptibility of pet animals under natural conditions and currently there is no SARS-CoV-2 epidemiological assessment occurrence in household ferrets. In this study, the presence of SARS-CoV-2 antibodies was evaluated in serum samples obtained from 127 household ferrets (Mustela putorius furo) in the Province of Valencia (Spain). Two ferrets tested positive to SARS-CoV-2 (1.57%) by in-house enzyme-linked immunosorbent assay based on receptor binding domain (RBD) of Spike antigen. Furthermore, anti-RBD SARS-CoV-2 antibodies persisted at detectable levels in a seropositive SARS-CoV-2 domestic ferret beyond 129 days since the first time antibodies were detected. This study reports for the first time the evidence of household pet ferrets exposure to SARS-CoV-2 in Spain to date.

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Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Seroprevalence in Household Domestic Ferrets (Mustela putorius furo)

Giner

Villanueva‐Saz

Tobajas

et al. 2021

Animals

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“…S2 and movie S1), and is complementary to strategies that target S1's functions or maintain S in its prefusion conformation, e.g., synthetic nanobodies (25,26). Fusion-inhibitory lipopeptides could be used for pre-and postexposure prophylaxis in combination with these strategies, and in conjunction with treatments [e.g., ribonucleoside analogs (27)] that reduce replication in a treated infected individual. A combination of drugs that target different aspects of the viral life cycle is likely ideal for this rapidly-evolving virus.…”

mentioning

confidence: 99%

Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets

Vries

Schmitz

Bovier

et al. 2021

Science

182

170

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Containment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection, and based on in vitro efficacy and in vivo biodistribution selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.

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“…1, 2). Molecular dynamics analysis and in vitro activity assays suggest that VR17-04 prevents GTP and UTP incorporation into the nascent RNA chain (2).…”

Section: Discussionmentioning

confidence: 99%

“…The primary outcome was measured as the time from the day of randomization (day 1) to an improvement of at least two score points (from the status at randomization) on the severity rating (SR) scale in days. The SR scale (WHO scale) is defined as 1 (8) -Death; 2 (7, 6) -Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3 (5) -Hospitalized, on non-invasive ventilation or high flow oxygen; 4 (5) -Hospitalized, requiring supplemental oxygen; 5 (3) -Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care; 6 (−) -Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care; 7 (2) -Not hospitalized, limitation on activities and/or requiring home oxygen; 8 (1) -Not hospitalized, no limitations on activities. Safety of enisamium iodide will be analysed based on the incidence of adverse events, vital signs, judgement of global tolerability on day of hospital discharge (separately by patient and investigator) and laboratory data when the study is completed.…”

Section: Methodsmentioning

confidence: 99%

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

Holubovska

Bojkova

Elli

et al. 2021

Preprint

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Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium’s antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.Significance statementSARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.

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Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets

Cited by 368 publications

References 31 publications

SARS-CoV-2 Seroprevalence in Household Domestic Ferrets (Mustela putorius furo)

SARS-CoV-2 Seroprevalence in Household Domestic Ferrets (Mustela putorius furo)

Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

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