Enisamium Inhibits SARS-CoV-2 RNA Synthesis

Elli, Stefano; Bojkova, Denisa; Bechtel, Marco; Vial, Thomas; Boltz, David A.; Muzzio, Miguel; Xiang, Peng; Sala, F.; Cosentino, Cesare; Goy, Andrew; Guerrini, Marco; Müller, Lutz; Cinatl, Jindrich; Margitich, Victor; Velthuis, Aartjan J.W. te

doi:10.3390/biomedicines9091254

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…Dwivedi et al’s docking and MD simulation confirmed their experimental results that holothurian sulfated glycans show potential effects against SARS-CoV-2 S protein RBD . Similar works include refs , , , and − . Other studies applied experiments to identify potent compounds and used docking to reveal interactions. − …”

Section: Methods and Approachesmentioning

confidence: 70%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus–host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein–protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.

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Section: Methods and Approachesmentioning

confidence: 70%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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“…Toxicology studies found no genotoxic effects of enisamium in an Ames test, no clastogenic activity in human peripheral lymphocytes with and without metabolic activation, no effect on the incidence of chromosome aberrations at any concentration, and no clinical signs of toxicity or cytotoxicity in bone marrow or micronuclei in Wistar rats at any dose. Following the promising results of enisamium in the treatment of influenza virus infection [ 14 , 15 , 16 ], we and others recently reported that enisamium can inhibit SARS-CoV-2 replication in Caco-2 and NHBE cells in vitro, while molecular dynamic simulations have suggested that the active compound of enisamium, VR17-04, can bind to the catalytic site of the SARS-CoV-2 RNA polymerase nsp12 [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial

Holubovska,

Babich,

Mironenko

et al. 2024

ARM

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Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo. The primary outcome was an improvement of at least two points on an eight-point severity rating (SR) scale within 29 days of randomization. We initially set out to study the effect of enisamium on patients with a baseline SR of 4 or 5. However, because the study was started early in the COVID-19 pandemic, and COVID-19 had been insufficiently studied at the start of our study, an interim analysis was performed alongside a conditional power analysis in order to ensure patient safety and assess whether the treatment was likely to be beneficial for one or both groups. Following this analysis, a beneficial effect was observed for patients with an SR of 4 only, i.e., patients with moderate COVID-19 requiring supplementary oxygen. The study was continued for these COVID-19 patients. Overall, a total of 592 patients were enrolled and randomized between May 2020 and March 2021. Patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. An analysis of the population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms (n = 33), the median time to improvement was 8 days for the enisamium group and 13 days for the placebo group (p = 0.005). For patients treated within 10 days of the onset of COVID-19 symptoms (n = 154), the median time to improvement was 10 days for the enisamium group and 12 days for the placebo group (p = 0.002). Our findings suggest that enisamium is safe to use with COVID-19 patients, and that the observed clinical benefit of enisamium is worth reporting and studying in detail.

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“…8 In addition to these reports, a recent in vitro study demonstrated that enisamium can also inhibit SARS-CoV-2 replication in cell culture and in vitro, while molecular dynamics simulation suggested that the active compound can bind in the catalytic site of the SARS-CoV-2 RNA polymerase non-structural protein 12. 9,10 To evaluate the efficacy and safety of enisamium in patients hospitalised with COVID-19, we conducted a phase 3 clinical trial in 14 clinical centers. We find that standard care in combination with enisamium treatment outweighs the effectiveness of standard care in combination with placebo treatment in patients with moderate COVID-19 requiring additional oxygen.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RNA polymerase inhibitor enisamium for treatment of moderate COVID-19 patients: a randomized, placebo-controlled, multicenter, double-blind phase 3 clinical trial

Holubovska

Babich²,

Mironenko

et al. 2022

Preprint

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Background Enisamium (trade name Amizon MAX) is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication and improves influenza patient recovery. We aimed to evaluate the clinical efficacy of enisamium treatment combined with standard care compared to standard care plus treatment with a placebo control in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. This trial was registered with ClinicalTrials.gov under NCT04682873. Methods The study was a phase three, multi-center, double-blind, randomized, placebo-controlled trial conducted in 14 clinical centers. Hospitalized patients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection were eligible. Patients were randomly assigned to receive either enisamium (500 mg per dose, 4 times a day) or a placebo. The treatment lasted ≤7 days in case of early discharge from the hospital, or loss of the patient's ability to swallow due to the need for ventilation. All patients received standard of care as deemed necessary by the investigator and the health status of each patient. All patients received standard of care as deemed necessary by the investigator and each patient's health status. The primary outcome was an improvement of at least two points on an 8-point, modified WHO severity rating (SR) scale within 29 days of randomization. The primary and safety outcomes were analyzed in accordance to the intention-to-treat (ITT) principle. Findings A total of 592 patients were enrolled and randomized between May 2020 and March 2021. Only patients with a baseline SR of 4 (285 subjects or 48.1%) were included in the ITT analysis. Patients with a baseline SR of 5 were excluded as the interim analysis did not show relevant differences between the enisamium group and placebo in this sub-group. The patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. No differences were observed between the safety or patient tolerability profiles of the enisamium and placebo treatment. Analysis of the ITT population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms, the median time to improvement was 8 for the enisamium group and 13 days for the placebo group (p = 0.0051). For patients treated within 7 days of the onset of COVID-19 symptoms, the median time to improvement was 10 days for the enisamium group and 11 days for the placebo group (p = 0.0035). Comparison of groups using a stratified one-sided Logrank criterion (adjustment using stratification by age categories: "<40 years", "40-<65 years" and "≥65 years") showed statistically significant differences between the groups (p = 0.00945, one-sided). Interpretation Enisamium is safe to use in COVID-19 patients. In COVID-19 patients that did not require supplementary oxygen (SR = 5), standard treatment was sufficient to aid recovery and enisamium did not offer significant clinical benefits. However, we found that standard care combined with enisamium offers a significant clinical benefit when given to patients with moderate COVID-19 requiring supplementary oxygen (SR = 4), if enisamium is given within 7 days of the onset of symptoms. These data suggest that enisamium therapy can be used as therapy against SARS-CoV-2 infection in these patients. Funding Farmak JSC, Wellcome Trust, and Royal Society.

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Enisamium Inhibits SARS-CoV-2 RNA Synthesis

Cited by 5 publications

References 33 publications

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial

RNA polymerase inhibitor enisamium for treatment of moderate COVID-19 patients: a randomized, placebo-controlled, multicenter, double-blind phase 3 clinical trial

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