Hong Kong research points to new route to treatments for coronavirus infection

Sammy Heung, South China Morning Post

Posted at Aug 08 2022 01:05 PM

A University of Hong Kong study, peer-reviewed and published by the authoritative British scientific journal Nature on Wednesday, outlines for the first time how coronaviruses including Covid-19, severe acute respiratory syndrome (Sars) and Middle East respiratory syndrome (Mers) boost their ability to reproduce themselves through exploitation of patients’ antiviral defence systems.

Researchers involved in the study say the discovery means more effective treatments for coronaviruses can be created.

Professor Yuen Kwok-yung, the lead researcher and a government health adviser, says the findings are an unexpected breakthrough in virology.

“We have worked on this study for seven years. When we saw the findings, we were very surprised. Why are the coronaviruses able to do so? This is a huge conceptual change in virology,” he told the Post. “No one has ever discovered this before.”

The Post unpacks the main findings of the study.

1. What did the study find out?

The study, carried out by academics including Yuen, found the coronaviruses could exploit a type of cysteine-aspartic protease called caspase-6 – an enzyme that breaks down protein – in an infected human body to facilitate viral replication.

It showed how these diseases could set off large-scale pandemics, while an inhibitor of caspase-6 could successfully limit the replication of the coronavirus.

The inhibitor was a chemical which could be bought from a foreign company, Yuen said.

When the inhibitor was used on mice infected with Mers, their survival rate was increased from 33.3 per cent to 80 per cent. Replication of Mers and lung damage caused by the virus were also significantly lowered in mice in which caspase 6 was eradicated.

The inhibitors also lowered the replication of Covid-19 and the inflammatory lung damage that it caused in hamsters.

There are at present seven known coronaviruses which can infect humans, including Covid-19, Sars and Mers.

The study only infected mice and hamsters with Covid-19 and Mers, but the inhibitors were found to be effective in disrupting the replication of all seven coronaviruses.

2. How does caspase-6 catalyse viral replication?

When an individual is infected with the coronaviruses, the human body triggers two crucial antivirus defence mechanisms – apoptosis and interferon reaction.

Caspase-6 in human and animal cells starts the apoptosis process, a programmed cell death that gets rid of infected cells and prevents them from turning into viral replication factories.

The infected cells, in normal circumstances, will at the same time secrete interferons which can hinder virus replication in the affected cells and lower the risk of infection in uninfected ones.

But caspase-6 will also break down a kind of protein contained in the coronaviruses. The fragments of the proteins will attach themselves to another type of protein in the host body and prevent it from starting the interferon reaction, promoting viral replication of the coronaviruses.

As caspase-6 is used to divide the proteins, the apoptosis process will also slow down.

3. What is the significance of the findings?

The research team said interferon reaction and the apoptosis process were the most crucial antivirus mechanisms in human and animal cells.

They highlighted that the study revealed “for the first time” how coronaviruses become “successful” pathogens.

It also showed how the coronaviruses “overcame” the antiviral defence mechanisms of the host cells by exploiting caspase-6, which was initially used for carrying out apoptosis as a defence against virus infection, to achieve better viral replication.

Yuen said the coronaviruses were “smarter” than the two mechanisms as they were able to halt the interferon reaction and slow down the apoptosis process.

“That is why the coronaviruses are so successful and are able to give rise to the pandemics, including the Sars one in 2003, the Covid-19 one from 2019 to now and Mers in the Middle East,” he told the Post.

“They are able to use the apoptosis pathway to combat the interferon pathway.”

Yuen said the findings were “a huge conceptual change” in virology and “unexpected”.

4. What do the findings mean for future coronavirus treatments?

The academics said the findings suggested that split viral proteins may counteract immune response, providing a fresh direction for viral protein research and related drug studies.

“These results further suggest that drugs can be designed against caspase-6, which can become a potential target of intervention for the antiviral treatment of all known human coronavirus infections,” they said.

Yuen said the inhibitor of caspase-6 were proven to be effective against all seven types of coronaviruses and hinted that the team were trying to produce a treatment based on the inhibitor.

“We hope we can modify the chemical inhibitor,” he said. “When you find a chemical, you need to reduce its toxicity, make sure it has an ideal rate of absorption and improve potency so that you can turn it into a medication.”

Yuen, however, said it was unclear when the medication would be ready for use.

5. How does the inhibitor differ from treatments for Covid-19 that are available in Hong Kong?

Yuen said the antiviral drugs used against Covid-19 at present targeted the virus itself, rather than enzymes in the human body such as caspase-6.

“The antiviral drugs we normally have … for example, molnupiravir targets the ribonucleic acid of the virus and Paxlovid targets the protease of the virus,” he said.

“The inhibitor we used targets the caspase-6 within the human body. Theoretically, there will not be antiviral drug resistance.”

Antiviral drug resistance happens when viruses are less susceptible to antivirals, which make treatments less successful.

Patients in Hong Kong with mild symptoms, who do not need to be admitted to hospital, are prescribed molnupiravir or Paxlovid, which are taken in pill form.

The Hospital Authority administers antiviral medication Remdesivir as well as monoclonal antibodies Casirivimab and Imdevimab to patients who are treated in public hospitals. Both treatments require infusion or injection.

The World Health Organization said Casirivimab and Imdevimab are combinations of antibodies that target the spike protein of the coronavirus and prevent it from infecting human cells.

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