New antivirals kill SARS-CoV-2

A study has found that newly engineered antiviral compounds can neutralize SARS-CoV-2, the virus that causes COVID-19, in human airway cells. The compounds also improved survival rates in mice infected with MERS.

Coronaviruses are a large group of viruses responsible for respiratory tract infections, ranging from the common cold to severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.

Although coronaviruses are a familiar threat, currently no vaccines or antiviral drugs can prevent or treat the infections in people.

The ongoing COVID-19 pandemic emphasizes the need for effective treatments and drug development. Scientists are hard at work, trying to find an antiviral agent effective against SARS-CoV-2.

Stay informed with live updates on the current COVID-19 outbreak and visit our coronavirus hub for more advice on prevention and treatment.

Much hope has been placed in remdesivir, an antiviral drug that was originally developed as a treatment for Ebola.

However, recent clinical practice guidelines developed by an international panel give only a “weak” recommendation for the drug in patients with severe COVID-19, and one recent study suggested that seaweed extract could be more effective.

Amid the continued search for a COVID-19 treatment, new research has homed in on a group of antiviral compounds that target an essential enzyme in coronaviruses.

The study’s authors report that the compounds drastically improved survival rates in a mouse model of MERS and neutralized SARS-CoV-2 in cells from people with COVID-19.

The findings appear in the journal Science Translational Medicine.

An essential protease

The research, led by scientists from Wichita State University, in Kansas, is based on the inhibition of a critical viral enzyme called 3C-like protease.

This enzyme is essential for the virus to replicate, and therefore survive, and given its crucial role, the enzyme is sometimes known simply as the “main protease.”

The researchers behind the present study specialize in making inhibitors of this enzyme and had previously developed an inhibitor, called GC376, that targets coronavirus infections in animals.

They showed that the compound could reverse the progression of severe feline infectious peritonitis, a coronavirus disease in cats that is fatal in every case. All the cats who received the drug for more than 2 weeks made a full recovery.

In light of the COVID-19 pandemic, the team redirected its focus to the novel coronavirus in humans, SARS-CoV-2.

They synthesized a number of antiviral compounds with activity against a range of coronaviruses. In the first line of tests, the compounds were screened for antiviral activity against MERS-CoV, SARS-CoV, and SARS-CoV-2.

They looked at the ability of the compounds to inhibit the 3C-like protease of these viruses, first in an isolated fashion, then inside cells. Since the protease has not been found in humans, it is a perfect target for an antiviral agent.

Stopping viral replication

The researchers found that two of the 22 compounds that they started with were of interest.

In particular, compound 6e was the most potent against SARS-CoV-2. This means that less of the compound was needed to inhibit the viral protease, compared with the other compounds tested.

Compound 6j was active against SARS-CoV-2 but particularly effective against MERS-CoV, at very low concentrations.

The researchers went on to confirm their findings in cells from the airways of people who had developed SARS-CoV-2 infections. The team found that cells treated with the antiviral compounds had lower viral loads, indicating that the virus’s ability to replicate had been suppressed.

In cells from two of the patients, the compounds reduced viral replication by 10 times. In the third patient, one of the compounds, 6j, was able to inhibit viral replication by 100 times.

At the time, a relevant mouse model of SARS-CoV-2 infection was still under development. There was, however, a mouse model for infection with MERS-CoV.

A treatment for MERS, too?

As well as finding a treatment candidate for SARS-CoV-2, the researchers describe a possible treatment for MERS, which continues to cause outbreaks and has a fatality rate of about 35%.

The researchers found that the same compound that they used in human airway cells, 6j, was able to inhibit the so-called main protease of MERS-CoV.

They went on to test the compound in a mouse model of MERS, administering it to some of the mice 1 day after they had been infected. The researchers found that every mouse that had received the antiviral survived, while those who did not died.

The treated mice fared better internally, with lower viral loads and significantly less lung damage than the mice that did not receive treatment. While the untreated mice had inflammation and congestion in their lungs, and in some cases collapsed lungs, the treated mice experienced limited damage.

Although this preclinical research does not demonstrate efficacy in humans — and though there are very marked clinical differences between MERS-CoV and SARS-CoV-2 infections in humans — it has established an exciting proof-of-concept for the team.

They plan to continue their research to see whether one of their compounds could treat both MERS and COVID-19 in people.

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