Outsmarting the Virus: Silesian scientists in International Project to Study SARS-CoV-2 Virus Key Enzyme
Scientists from the Silesian University of Technology in Gliwice are working in an international team studying one of the key enzymes of the coronavirus. The team's results focus on mechanisms that inhibit the multiplication of the pathogen.
The Tunneling Group led by Dr. Artur Góra from the Biotechnology Centre of the Silesian University of Technology, in cooperation with researchers from the University of Alberta in Canada and the Polytechnic University of Turin in Italy, characterized the main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) and compared it with the corresponding enzyme of the virus causing SARS ( SARS-CoV Mpro).
“Initially, we wanted to compare the behaviour of both enzymes and on this basis propose previously tested compounds that could be quickly introduced to inhibit the activity of the main protease, and thus inhibit the multiplication of the virus. Unfortunately, it turned out that during the preliminary analyses the pocket binding the substrate, in which the compounds inhibiting the enzyme action would be binding, was very mobile, meaning that we cannot take the shortcut,” says Dr. Artur Góra.
He added: “In addition, we have observed that our molecular target can easily change, because it is characterized by high evolutionary variability. This would mean that all our and our partners' effort could be wasted. That is why we immediately started work on selecting another, evolutionarily stable and less mobile region of the Mpro protein, to which potential drugs could bind more effectively.
“We want to outsmart the virus and predict the next possible ways of its evolution. We already know that the virus isolated in Italy differs from that from Wuhan. Mutations leading to changes in the sequence of the main protease are also only a matter of time and we want to be well prepared for this eventuality.”
Scientists can quickly check the binding efficiency of selected compounds thanks to a modern platform for high-throughput analysis of intermolecular interactions provided by NanoTemper. Góra said: “We can talk about huge luck in this situation: we received a grant to obtain unique research infrastructure at the end of last year and using MonolithNT.Automated we are able to verify several hundred compounds per day.”
Work towards the characterization of SARS-CoV-2 Mpro began when the crystallographic structure of this protein became available. Based on it, molecular dynamics simulations were performed, which were then analysed for changes in protein dynamics and behaviour.
Researchers from the Tunneling Group have created the program AQUA-DUCT that enables analysis of the dynamics of protein behaviour taking into account changes in available intramolecular spaces, which is usually omitted in conventional analysis. In addition, research has been extended to include evolutionary analysis of Mpro viral proteins and protein stability.
The first research results of Dr Góra's team were made available at the beginning of March.
The members of the Silesian University of Technology research team also include PhD students: Karolina Mitusińska from the Biotechnology Centre and the Faculty of Chemistry, Maria Bzówka from the Joint Doctoral College, Agata Raczyńska and Aleksandra Samol from the Faculty of Automatic Control, Electronics and Computer Science.
PAP - Science in Poland, Anna Gumułka
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