Researchers reported that remdesivir potently inhibited SARS-CoV-2

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The news about remdesivir, the investigational anti-viral drug that has shown early promise in the fight against COVID-19, keeps getting better.

This week researchers at Vanderbilt University Medical Center (VUMC), the University of North Carolina at Chapel Hill and Gilead Sciences reported that remdesivir potently inhibited SARS-CoV-2, the virus which causes COVID-19, in human lung cell cultures and that it improved lung function in mice infected with the virus.

These preclinical findings help explain the clinical effect the drug has had in treating COVID-19 patients.

Remdesivir has been given to patients hospitalized with COVID-19 on a compassionate use basis since late January and through clinical trials since February.

In April, a preliminary report from the multicenter Adaptive COVID-19 Treatment Trial (which included VUMC) suggested that patients who received the drug recovered more quickly.

“All of the results with remdesivir have been very encouraging, even more so than we would have hoped, but it is still investigational, so it was important to directly demonstrate its activity against SARS-CoV-2 in the lab and in an animal model of disease,” said VUMC’s Andrea Pruijssers, Ph.D.

Pruijssers, research assistant professor of Pediatrics at VUMC and lead antiviral scientist in the laboratory of Mark Denison, MD, is the paper’s co-corresponding author with Timothy Sheahan, Ph.D., assistant professor of Epidemiology at UNC-Chapel Hill.

Denison, the E.C. Stahlman Professor of Pediatrics at VUMC, directs the Division of Pediatric Infectious Diseases. He and Ralph Baric, Ph.D., the William R. Kenan, Jr. Distinguished Professor of Epidemiology at UNC-Chapel Hill, and colleagues have been studying remdesivir since 2014.

They were the first to perform detailed studies to demonstrate that the drug, which was developed by Gilead Sciences to combat hepatitis C and respiratory syncytial virus, and later the Ebola virus, also showed broad and highly potent activity against coronaviruses in laboratory tests.

The current findings, reported this week in the journal Cell Reports, provide “the first rigorous demonstration of potent inhibition of SARS-CoV-2 in continuous and primary human lung cultures.” The study is also the first to suggest that remdesivir can block the virus in a mouse model.

Ongoing clinical trials will determine precisely how much it benefits patients in different stages of COVID-19 disease.

Meanwhile in the laboratory, Pruijssers said, “We also are focusing on how to use remdesivir and other drugs in combinations to increase their effectiveness during COVID-19 and to be able to treat at different times of infection.”

COVID-19, which to date has infected more then 12 million people and killed nearly 600,000 worldwide, is at least the third instance since 2003 in which a coronavirus originally transmitted from bats has caused serious illness in humans.

Thus there is an urgent need to identify and evaluate broadly efficacious and robust therapies that can limit and prevent coronavirus infections. “Broad-spectrum antiviral drugs, antibodies, and vaccines are needed to combat the current pandemic and those that will emerge in the future,” the researchers said.

In addition to SARS-CoV-2, studies in the Denison and Baric labs have shown that remdesivir is effective against a vast array of coronaviruses, including other bat viruses that could emerge in the future in humans.

“We hope that will never happen, but just as we were working to characterize remdesivir over the past six years to be ready for a virus like SARS-CoV-2, we are working and investing now to prepare for any future coronavirus,” Denison said. “We want remdesivir and other drugs to be useful both now and in the future.”


Antiviral Agents

Remdesivir
Remdesivir is a potential drug for treatment of COVID-19. It is a phosphoramidate prodrug of an adenosine C-nucleoside and a broad-spectrum antiviral agent synthesized and developed by Gilead Sciences in 2017 as a treatment for Ebola virus infection [28].

Remdesivir is metabolized into its active form, GS-441524, that obscures viral RNA polymerase and evades proofreading by viral exonuclease, causing a decrease in viral RNA production. The antiviral mechanism of remdesivir is a delayed chain cessation of nascent viral RNA.

Animal experiments indicate that remdesivir can effectively reduce the viral load in lung tissue of mice infected with MERS-CoV, improve lung function, and alleviate pathological damage to lung tissue [29].

Wang et al. found that remdesivir potently blocks SARS-CoV-2 infection at low range of micromolar concentrations and has a high selectivity index (half-maximal effective concentration (EC50), 0.77 μM; half-cytotoxic concentration (CC50) > 100 μM; SI > 129.87) [30•].

Holshue et al. reported that IV administration of remdesivir yielded promising results in the treatment of a patient with COVID-19 recovering from pneumonia in the USA [31]. In order to evaluate the efficacy and safety of the drug in patients with COVID-19, a randomized, placebo-controlled, double-blind, multicenter, phase III clinical trial was launched on February 5, 2020 in China.

Patients in the experimental group received an initial dose of 200 mg of remdesivir and a subsequent dose of 100 mg for 9 consecutive days via intravenous infusion in addition to routine treatment. Patients in the control group received same dose of placebo treatment.

The trial is expected to conclude by the end of April 2020. The number of cases planned to be enrolled is 308 and 452, respectively [32, 33]. Current recommendation for remdesivir includes a 10-day regimen of remdesivir treatment: 200 mg loading dose on day 1, followed by 100 mg once-daily maintenance doses for 9 days in both studies.

This regimen of remdesivir therapy is similar to that of former randomized clinical trial against the Ebola virus [32, 33]. In a summary of subjects receiving remdesivir via compassionate use in the USA, nearly 70% of patients had improvement in terms of oxygen requirements and many patients that were mechanically ventilated were extubated.

This report did not include a control group; therefore, extrapolating these results is difficult. It is too early to conclude the direct antiviral effect of remdesivir on the enhanced clearing of viral loads in the respiratory tract, but it indeed suggests a promising therapeutic effect of remdesivir [34].

Hydroxychloroquine and Chloroquine
Chloroquine and hydroxychloroquine are drugs with a long history of clinical use with similar chemical structures often used in the treatment of lupus erythematosus, rheumatoid arthritis, and malaria [35].

Compared with chloroquine, hydroxychloroquine has a hydroxyl group, which makes it less toxic while maintaining similar activity. One mechanism of action of chloroquine and hydroxychloroquine is targeting lysosome which may be useful to control graft-versus-host disease in humans [36].

With the accumulation of chloroquine in lysosomes, the pH of lysosomes is significantly changed and the activity of proteases in lysosomes is directly affected, thus affecting the degradation of proteins and glycosaminoglycan [36, 37].

Chloroquine can inhibit the entry of SARS-CoV-2 and prevent virus-cell fusion by interfering with glycosylation of ACE2 receptor and its binding with spike protein, suggesting that chloroquine treatment might be more effective in the early stage of infection, before COVID-19 reduces ACE2 expression and activity [30, 38, 39].

Hydroxychloroquine possesses anti-inflammatory effect on Th17-related cytokines (IL-6, IL-17, and IL-22) in healthy individuals, and systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients [40].

There is some evidence that chloroquine and hydroxychloroquine can reduce cytokine storm. According to one analysis, the main cause of death of COVID-19 patients is related to the triggering of the cytokine storm, which contributed to acute respiratory distress [41]. It has been reported that hydroxychloroquine is effective in inhibiting SARS-CoV-2 infection in vitro [1, 39, 42].

Zinc inhibits SARS-CoV and retrovirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture [43]. There is also evidence that zinc enhances chloroquine intracellular uptake [44].

As such, combining zinc with chloroquine or hydroxychloroquine is intriguing and is currently under investigation. Overall, more clinical trials are underway to evaluate the safety and efficacy of hydroxychloroquine as a prophylactic and treatment for COVID-19.

The US FDA has issued emergency authorization for the use of chloroquine and hydroxychloroquine for the treatment of COVID-19. A recent study by Tang et al. reported that hydroxychloroquine did not lead to higher negative conversion rates, but had reduced clinical symptoms through the anti-inflammatory properties and recovery of lymphopenia [45•].

It has also been reported that high doses of chloroquine (600 mg twice daily for 10 days or total dose of 12 g) may be associated with significant cardiac risks and should not be recommended for treating COVID-19 [46•]. There is still a lack of evidence regarding the safety and effectiveness of these agents in treating COVID-19. In this regard, clinicians and patients should be made aware of the risk versus benefit profile of these medications [47].

Lopinavir-Ritonavir
Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Lopinavir is marketed and administered exclusively in combination with ritonavir. This combination was first marketed by Abbott under the brand name Kaletra in 2000 [48].

Due to lopinavir’s poor oral bioavailability and extensive biotransformation, it is co-formulated with ritonavir to enhance its exposure. Ritonavir is a potent inhibitor of the enzymes that are responsible for lopinavir metabolism, and its co-administration “boosts” lopinavir exposure and improves antiviral activity [48].

Lopinavir is a peptidomimetic molecule, containing a hydroxyethylene scaffold that mimics the peptide linkage typically targeted by the HIV-1 protease enzyme but which by itself cannot be cleaved, thus preventing the activity of the HIV-1 protease [49].

Lopinavir-ritonavir was investigated in an open-label, individually randomized, controlled trial, where patients with COVID-19 received either lopinavir-ritonavir 400 mg/100 mg, orally twice daily plus standard of care, or standard of care alone.

No benefit was observed with lopinavir-ritonavir treatment beyond standard care. Diarrhea, nausea, and asthenia were the most frequently reported adverse effects in patients receiving lopinavir-ritonavir-based regimen [50].

Interestingly, in a report from Korea, lopinavir-ritonavir administration significantly decreased coronavirus titers with no or little coronavirus titers were observed in the follow-up study. However, the analysis included a single patient in the initial phase of outbreak in Korea [51].

Umifenovir (Arbidol)
Umifenovir (branded as Arbidol), a derivative of indole carboxylic acids, was first developed in 1988 in Russia and has since been approved in Russia and China for treating prophylaxis and infections associated with influenza A and B, and other arbovirus [52].

Later on, umifenovir demonstrated in vitro antiviral efficacy in widely spreading virus strains such as the Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus [53].

Its major mechanism of action is to block the virus-cell membrane fusion as well as virus-endosome fusion through incorporation into cell membranes and interference with the hydrogen bonding network of phospholipids [54].

In influenza virus, it has been shown to directly interact with virus particles to stabilize hemagglutinin (HA), reducing the likelihood of reaching the low pH threshold required for conformational transition into functional fusogenic HA [55]. Blaising et al. reported the in vitro activity of umifenovir against SARS-CoV-1 and SARS-CoV-2 [56, 57].

A retrospective cohort study has reported that compared with lopinavir-ritonavir (LPV-RTV) only group, combination of umifenovir and LPV-RTV has shown increased negative conversion rate of SARS-CoV-2 and improved chest CT scan results [58].

However, another prospective study (ChiCTR200030254) has shown that compared with favipiravir, umifenovir has inferior outcome in clinical recovery rate and relief of fever and cough [59].

There are two randomized and open-label trials ongoing in China, investigating the efficacy and safety of umifenovir against COVID-19. The effect of umifenovir plus standard treatment versus LPV-RTV plus standard treatment will be evaluated in NCT04252885, and the effect of umifenovir plus standard treatment versus standard treatment will be tested in NCT04260594.

Favipiravir (Avigan)
Favipiravir (branded as Avigan) has been developed by Fujifilm Toyama Chemical in 2014 in Japan for the treatment of avian influenza or novel influenza resistant to neuraminidase inhibitors.

It is a guanine analogue with pyrazinecarboxamide structure, and its antiviral activity is decreased at the presence of purine nucleosides due to the competition [60]. The prodrug favipiravir first enters the infected cells through endocytosis and is then transformed into active favipiravir ribofuranosyl phosphates through phosphoribosylation and phosphorylation [60, 61].

The antiviral activity is exhibited through selectively targeting conservative catalytic domain of RNA-dependent RNA polymerase (RdRp), interrupting the nucleotide incorporation process during viral RNA replication [60]. The dysregulation in viral RNA replication results in increased number and frequency of transition mutations including replacement of guanine (G) by adenine (A) and cytosine (C) by thymine (T) or C by Uracil (U) which induces destructive mutagenesis in RNA viruses [60].

Favipiravir has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus [62]. Recent in vitro and human studies have repurposed favipiravir as an experimental agent against enveloped, positive-sense, single-strand RNA virus SARS-CoV-2.

An in vitro research has investigated seven potential anti-SARS-CoV-2 medicines including ribavirin, penciclovir, favipiravir, nafamostat, nitazoxanide, remdesivir, and chloroquine, showing that remdesivir and chloroquine have favorable selectivity index [30]. In addition, the study showed favipiravir has exerted efficacy in Vero E6 cells infected with SARS-CoV-2 with half-maximal effective concentration (EC50) of 61.88  μM and half-cytotoxic concentration (CC50) at over 400 μM, implying the high concentration is needed for safe and effective treatment [30].

Clinical trials testing favipiravir against COVID-19 have been carried out vigorously in various countries including China and Japan. A randomized control trial (ChiCTR200030254) has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%) than that treated with umifenovir (55.86%), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group [59].

Up to mid-April 2020, there are eight undergoing clinical trials in China and two in Japan examining the anti-SARS-CoV-2 potential of favipiravir. These trials include non-randomized and randomized controlled trials evaluating the efficacy and safety of favipiravir alone (ChiCTR2000030113, JPRN-jRCTs031190226, JPRN-jRCTs041190120) or in conjunction with interferon-α (ChiCTR2000029600), baloxavir marboxil (ChiCTR2000029544, ChiCTR2000029548), tocilizumab (ChiCTR2000030894, NCT04310228), or chloroquine phosphate (ChiCTR2000030987, NCT04319900).

Oseltamivir (Tamiflu)
Oseltamivir(branded as Tamiflu) is a drug approved for treatment of influenza A and B. Oseltamivir targets the neuraminidase distributed on the surface of the influenza virus to inhibit the spread of the influenza virus in the human body [63, 64].

A study in Wuhan reported that no positive outcomes were observed after receiving antiviral treatment with oseltamivir [65]. Several clinical trials are still evaluating the effectiveness of oseltamivir in treating SARS-CoV-2 infection. Oseltamivir is also used in clinical trials in several combinations, such as with chloroquine and favipiravir [66].

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More information: Andrea J. Pruijssers et al, Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice., Cell Reports (2020). DOI: 10.1016/j.celrep.2020.107940

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