FNP Prize Winner deciphers an enzyme critical in the fight against SARS-CoV-2

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Prof. Marcin Drąg from the Wrocław University of Science and Technology and his team have deciphered an enzyme whose activity may be crucial in the fight against the SARS-CoV-2 coronavirus. “If we treat this enzyme as a lock, we have just made a key to it,” says Drąg in his conversation with the Polish Press Agency.

“This is the most important protein – among the many identified – that companies looking for a high-speed diagnostic test have hinted at,” says Prof. Marcin Drąg from the Wrocław University of Technology, winner of the 2019 Foundation for Polish Science Prize in chemical and material sciences.

The research of Wrocław scientists provides a basis for the search for a COVID-19 drug.

The enzyme studied by the team – SARS-CoV-2 Mpro protease – cleaves the proteins found in the virus. “This enables the virus to survive. The inhibition of this enzyme makes the virus die,” explains Drąg.

“If we design a drug that inhibits the activity of this enzyme, we will practically kill the coronavirus. This was the case in the last coronavirus epidemic, SARS,” says the scientist.

“If we treat this enzyme as a lock, we have just made a key to it,” claims Drąg, adding that the enzyme was previously known, but countless combinations of “keys” existed. “We have managed to find the key that fits this particular enzyme,” he clarifies.

Drąg explains how the researchers obtained the enzyme crucial to the coronavirus, and how they knew it was so important. “For several years, we have been working with professor Rolf Hilgenfeld’s group from the Lübeck University in Germany. I published a paper with the professor during the Zika virus epidemic and, more recently, a publication about the dengue and the West Nile virus. Professor Hilgenfeld had an immense influence in the stopping of the previous SARS epidemic,” says Drąg. During the SARS pandemic of 2002/2003, Hilgenfeld presented a three-dimensional structure of the SARS virus protease and its first inhibitor. Several years later, a statue was even erected in Singapore to commemorate this event.

“In early February this year, as soon as Professor Hilgenfeld obtained the enzyme – the coronavirus SARS-CoV-2 protease – he brought it to my laboratory in Wrocław, and we began to study it very thoroughly,” says Drąg. He adds that the protease of the current SARS-Cov2 virus is very similar to that of the 2002 SARS-CoV virus, on which Hilgenfeld previously worked.

As Drąg explains, it is a unique enzyme (it “recognizes glutamine in P1 position”). “There are practically no such enzymes in humans,” says the researcher. Therefore, we can expect that potential drugs targeting this enzyme will harm the virus but not humans, which means they will be less toxic.

The publication (including study results) of Drąg’s team is still under review, but the team has already made the results available to scientists from all over the world, completely free of charge. “We did not patent our findings. The preprint is available online. It is a gift from my laboratory to all those who are interested,” emphasizes the scientist. A few days after the publication, there is no shortage of interested parties. Teams from different parts of the world submit their questions and proposals for cooperation.

“What we have just published is one of the most important pieces of information that we can gain about this enzyme: its complete substrate preference,” specifies Drąg. The research shows to which amino acids the enzyme binds itself in key positions. “We can determine if these amino acids are large, small, hydrophobic, or alkaline. We can also map the main part of the enzyme and adapt the drugs that are already on the market,” explains Drąg.

He adds that chemists or companies can now use this research to create new bioactive compounds for the SARS-CoV2 virus. The compound can even prove useful for companies developing diagnostic tests to more quickly determine if somebody has the coronavirus.

“We are now focusing on other proteins found in this virus, not just proteases. Our work is proceeding at a remarkable pace,” stresses Drąg.

The researchers were able to conduct the research so rapidly thanks to Drąg’s previously elaborated new technological platform for obtaining biologically active compounds, proteolytic enzyme inhibitors in particular.

Drąg’s Hybrid Combinatorial Substrate Library (HyCoSuL) allows scientists to design and obtain highly active and selective chemical tools. The technology platform employs a wide range of unnatural amino acids to monitor the activity of proteolytic enzymes. It can be used to develop new therapies, medicines, or diagnostic methods. It is for this research that Drąg received the 2019 Foundation for Polish Science Prize.

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Source: PAP – Nauka w Polsce, Ludwika Tomala

Photo: Prof. Marcin Drąg, phot. Magdalena Wiśniewska-Krasińska