02.11.2020 change 02.11.2020

Polish scientists closer to finding new drugs for COVID-19 patients

Credit: Fotolia Credit: Fotolia

Compounds that have the potential to become drugs for COVID-19 have been identified by an international team of scientists led by Professor Marcin Drąg from the Wrocław University of Science and Technology.

Publishing their findings in the prestigious journal Nature Chemical Biology, scientists tested compounds that strongly inhibit the activity of one of the enzymes of the SARS-CoV-2 coronavirus (Mpro protease), and consequently the replication of the virus, on human liver cells infected with the coronavirus.

Professor Drąg said: “The protease inhibitor we identified turned out to be virtually as powerful as remdesivir (an antiviral drug currently approved for use in people with severe COVID-19 - ed.), but less toxic to human cells.”

In his opinion, this gives hope that in the future it will be possible to effectively use a cocktail of drugs in the treatment of COVID-19 patients. 

Remdesivir works differently (it is an inhibitor of an enzyme called RdRP - RNA-dependent RNA polymerase). 

Drąg’ added: “If we could administer a cocktail of several drugs, as in the treatment of people with HIV, we would certainly be able to treat COVID-19 patients much faster.”

In the first half of 2020, Professor Drąg and his team showed that the SARS-CoV-2 virus proteases - Mpro and PLpro - are identical in the so-called active site with the proteases of the SARS-CoV-1 virus, which caused the epidemic in 2002-2003. An active site is a fragment of an enzyme molecule to which a substrate (a compound undergoing a chemical reaction) binds, as do drugs designed to block the action of the enzyme.

The Mpro and PLpro proteases are crucial in the process of coronavirus replication. Additionally, the PLpro protease prevents infected human cells from defending themselves against the infection. These enzymes are therefore excellent targets for drugs that can suppress viral infection. Viral protease inhibitors are used, for example, in the treatment of HIV patients.

Drąg said: “The information that the proteases of SARS-CoV-1 and SARS-CoV-2, which triggers COVID-19, are generally identical in the active site was critical. For groups of scientists working on anti-SARS drugs, it was a signal that the same drugs could be tested for the new coronavirus', 

The scientists also managed to identify new compounds that strongly inhibit SARS-CoV-2 virus proteases. The Mpro protease inhibitor was tested in Professor Drąg's lab and then sent to the laboratory of Professor Johan Neyts in Leuven, Belgium. There, in tests on human liver cells infected with SARS-CoV-2, it has been confirmed that it also works as well as remsedivir. Importantly, it is less toxic to human cells.

In the next stage, the compound was tested in the laboratory of Professor Rolf Hilgenfeld from the University of Lübeck in Germany, where its crystal structure was deciphered and shown to actually bind to the active site of the Mpro protease.

In turn, Professor Wojciech Młynarski's team from the Medical University of Lodz checked how the Mpro protease inhibitor behaved in biological material collected directly from people suffering from COVID-19. Cell samples were collected from the throat of COVID-19 patients. With the help of Professor Drąg's special marker (used to connect the inhibitor to a fluorescent marker), researchers checked how the Mpro protease reacted with the inhibitor.

A few days earlier (October 16), in the journal Science Advances, Drąg's team also described two inhibitors of the second coronavirus SARS-CoV-2 protease, PLpro. They act selectively on the viral enzyme, but not on human proteases. This significantly reduces the risk of side effects when administered to patients.

Professor Drąg emphasises that the fact that the proteases of SARS-CoV-1 and SARS-CoV-2 viruses are almost identical in the active site means that they are well conserved (they do not mutate in the active site). This significantly reduces the risk that the virus will become resistant to drugs from the protease inhibitors group.

Drąg said: “This is great news because it also means that when we develop a drug that will act on SARS-CoV-2, we will also be able to use it in the event of another epidemic caused by another coronavirus from the same class', the specialist notes. Further coronavirus pandemics are just a matter of time.

“We have to be prepared for this and have drugs. Otherwise, it will be necessary to develop a vaccine again, which will take months or years.”

He added that the SARS-CoV-2 vaccines under development are expected to induce an immune response against the S protein or the N protein of the coronavirus. But these proteins mutate very strongly, so in the case of another pandemic it will be necessary to create a new vaccine.

Prof. Drąg and his colleagues used the knowledge of both proteases for drug retargeting (searching for new uses of existing drugs). 

Drąg said: “We have determined that numerous analogues of the well-known drug ebselene work very well on both enzymes.

“We are currently testing them in virology laboratories. The preliminary information shows that many of them work great.”

Find out more about this research on THIS page.

PAP - Science in Poland

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