Another key enzyme for the function of SARS-CoV-2 virus is very similar to the enzyme known from SARS-CoV-1, Prof. Marcin Drąg and his team just announced. This means that the study of this enzyme conducted as part of the fight against the SARS epidemic can be used to look for a drug for COVID-19.
In mid-March 2020, the laureate of the Foundation for Polish Science Prize, Marcin Drąg and his team from the Wrocław University of Technology, worked out the enzyme – the SARS-CoV-2 Mpro protease – which may be key to fighting the SARS-CoV-2 coronavirus. “If we treat the enzyme as a lock, we have acquired the key to it,” Drąg said at the time. Now Drąg has announced another breakthrough result: his team was the first in the world to develop another protease, whose blocking causes the inhibition of the virus. This is the SARS-CoV-2-PLpro protease.
“The coronavirus causing COVID-19 has two proteases. Stopping one of them stops virus replication one hundred percent. This is confirmed medical data. And we are the only laboratory in the world that now has both these proteases in an active form and well profiled,” Drąg explains with satisfaction.
He reminds us that the current SARS-CoV-2 virus is a close cousin of the SARS-CoV-1 virus, which caused the SARS epidemic in 2002. At that time, many groups around the world worked to understand the effects of the virus. However, until the mechanisms of functioning of the virus causing COVID-19 are known, we do not know which past research on SARS can be used directly; e.g. in researching a new drug or retargeting (searching for new applications) of already known drugs.
“And we have now been able to compare PLpro proteases from the ‘old’ and the ‘new’ SARS-CoV virus. We have shown that they are very similar in the specificity of substrate binding, which is key information about the virus’ activity,” Drąg explains. “That’s excellent news. Thanks to this, all information obtained over many years of research on the previous SARS can be immediately used in research on the control of SARS-CoV-2,” he concludes.
His team has already shown several examples of compounds that selectively inhibit this enzyme.
“It just so happens that the PLpro protease from the previous SARS virus was the first viral protease that I studied in my career. Thanks to this, I knew who had expertise in these proteins and with whom to cooperate,” explains Drąg. And he adds that his job was not to prepare the protein but to understand how it works.
“I activated all the contacts I had in the world to get this enzyme for research,” he says. And he succeeded. The laboratory of Prof. Shaun Olsen from South Carolina worked three weeks to prepare the protein. The enzyme arrived in Poland on Good Friday, just before Easter, but there was a danger that the parcel could reach Wrocław only after the holiday, on Wednesday. “And if this enzyme waited so long before we could use it, it would completely lose its activity; it would become deactivated. Fortunately, however, the customs office and the courier company showed great understanding. Thanks to two people from the Polish FedEx who spent a few hours on the phone with me, the enzyme reached our laboratory before Easter. And on Wednesday next week, we practically had all the results ready,” Drąg describes the race against time.
SARS-CoV-2 is made up of 29 different proteins, including two proteases: SARS-CoV-Mpro and SARS-CoV-2-PLpro. Proteases are considered to be a difficult but very good target for seeking drugs against viruses. For example, some HIV, hepatitis C, type 2 diabetes, and new generation anti-cancer drugs are based on knowledge about proteases.
The SARS-Cov-2-PLpro protease studied by Drąg is not only necessary for the virus’ replication but also blocks the body’s defense mechanism against this pathogen. This enzyme stops the mechanisms that lead to the death of the infected cell. “The coronavirus uses this enzyme to deceive human cells so that it can replicate and create a huge number of copies,” explains Drąg. Therefore, it seems that blocking this protein could help the body fight the virus.
As in the case of previous studies, also this time Drąg decided to share his results for free, without patenting. An article with research results is under review, but the preprint of the publication is available online to everyone free of charge.
Drąg emphasizes that several research groups from the USA participated in the research on SARS-Cov-2-PLpro. Besides the group of Prof. Shaun Olsen (Medical University of South Carolina / University of Texas Health Science Center at San Antonio), these were Prof. Tony Huang and Dr. Miklos Bekes (New York University School of Medicine), and Scott Snipas (Sanford Burnham Prebys Medical Discovery Institute, California).
Source: PAP – Science in Poland, Ludwika Tomala.
Photo: Prof. Marcin Drąg_fot.Magdalena Wiśniewska-Krasińska.