q&more
My watch list
my.chemie.de  
Login  

News

Possible Achilles’ heel of SARS-CoV-2 virus identified

Anti-viral strategy with double effect

pixabay.com/Unsplash

Symbolic image

31-Jul-2020: When the SARS-CoV-2 virus penetrates human cells, it lets the human host cell produce proteins for it. One of these viral proteins, called PLpro, is essential for the replication and rapid spread of the virus. An international team of researchers led by Goethe University and University Hospital Frankfurt has now discovered that the pharmacological inhibition of this viral enzyme not only blocks virus replication but also strengthens the anti-viral immune response at the same time.

In the case of an infection, the SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defense. During this process, infected body cells release messenger substances known as type 1 interferons. These attract natural killer cells, which kill the infected cells.

One of the reasons the SARS-CoV-2 virus is so successful – and thus dangerous – is that it can suppress the non-specific immune response. In addition, it lets the human cell produce the viral protein PLpro (papain-like protease). PLpro has two functions: It plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. The German and Dutch researchers have now been able to monitor these processes in cell culture experiments. Moreover, if they blocked PLpro, virus production was inhibited and the innate immune response of the human cells was strengthened at the same time.

Professor Ivan Đikić, Director of the Institute of Biochemistry II at University Hospital Frankfurt and last author of the paper, explains: “We used the compound GRL-0617, a non-covalent inhibitor of PLpro, and examined its mode of action very closely in terms of biochemistry, structure and function. We concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. The further development of PLpro-inhibiting substance classes for use in clinical trials is now a key challenge for this therapeutic approach.”

Another important finding from this work is that the viral protein PLpro of SARS-CoV-2 cleaves off ISG-15 (interferon-stimulated gene 15) from cellular proteins with a higher level of activity than the SARS equivalent, which leads to greater inhibition of type I interferon production. This is concordant with recent clinical observations which show that COVID-19 exhibits a reduced interferon response in comparison to other respiratory viruses such as influenza and SARS.

To understand in detail how inhibiting PLpro stops the virus, researchers in Frankfurt, Munich, Mainz, Freiburg and Leiden have worked closely together and pooled their biochemical, structural, IT and virological expertise.
Donghyuk Shin, postdoctoral researcher and first author of the paper, says: “Personally, I would like to underline the significance of science and research and in particular emphasize the potential generated by a culture of collaboration. When I saw our joint results, I was immensely grateful for being a researcher.”

Professor Sandra Ciesek, Director of the Institute of Medical Virology at University Hospital Frankfurt, explains that the papain-like protease is an extremely attractive anti-viral goal for her as a physician because its inhibition would be a “double strike” against SARS-CoV-2. She highlights the excellent collaboration between the two institutes: “Especially when investigating a new clinical picture, everyone profits from interdisciplinary collaboration as well as different experiences and viewpoints.”

Original publication:
Donghyuk Shin et al.; "Inhibition of papain-like protease PLpro blocks 1 SARS-CoV-2 spread and 2 promotes anti-viral immunity"; Nature; 2020

Facts, background information, dossiers

  • SARS-CoV-2
  • coronaviruses
  • Covid-19

More about Uni Frankfurt am Main

  • News

    How particulate matter arises from pollutant gases

    When winter smog takes over Asian mega-cities, more particulate matter is measured in the streets than expected. An international team, including researchers from Goethe University Frankfurt, as well as the universities in Vienna and Innsbruck, has now discovered that nitric acid and ammoni ... more

    Pool testing of SARS-CoV-02 samples increases worldwide test capacities many times over

    Researchers at the German Red Cross Blood Donor Service in Frankfurt headed by Professor Erhard Seifried, and the Institute for Medical Virology at the University Hospital Frankfurt at Goethe University headed by Professor Sandra Ciesek succeeded in developing a procedure that makes it poss ... more

    Toxin responsible for Legionella growth identified

    A team of scientists led by EMBL group leader Sagar Bhogaraju and Ivan Dikic of Goethe University, Frankfurt, discovered that the toxin SidJ in Legionella bacteria enforces a unique modification on human proteins and helps legionella grow inside human cells. SidJ hijacks human protein Calmo ... more

  • q&more articles

    From feast to famine and back – no problem for bacteria

    Bacteria are true survivors. In the course of evolution, they have developed numerous strategies to adapt to rapidly changing, uncertain environmental conditions. Their metabolism is much more sophisticated than that of human beings. Within minutes they can regulate their gene expression an ... more

    Why biosimilars and not biogenerics?

    Medicines produced using genetic techniques have existed since 2006, called “similar biological medicinal products” or “biosimilars”. Until a year ago, this was a fairly low-profile group, even in expert circles. This has all changed now, however, with the recent licensing of the first bios ... more

    Paradigm shift

    What would medicine be without drugs? But are these drugs being used optimally today? Not at all, as we now know thanks to the findings of molecular medicine. Because for the use of these drugs, it is important to observe two aspects: the disease and the patient. Only slowly is it becom ... more

  • Authors

    Prof. Dr. Jörg Soppa

    Jörg Soppa, born in 1958, studied biochemistry in Tübingen and then went on to do his doctorate at the Max Planck Institute of Biochemistry in Martinsried near Munich. In 1990 he established his own research group there and held courses at the Institute of Genetics and Microbiology of Munic ... more

    Prof. Dr. Heinfried H. Radeke

    Heinfried H. Radeke studied medicine at the Hannover Medical School (MHH) and received his medical license in 1985. His Ph.D. thesis was recognized as the best research dissertation of 1986. After two years as an assistant physician at the Göttingen University Hospital, he began his career ... more

    Prof. Dr. Theo Dingermann

    Theodor Dingermann, born 1948, studied pharmacy in Erlangen ­and received his doctor title in 1980 to become Dr. rer. nat. In 1990 he was offered the C4 professorship at the Institute for Pharmaceutical Biology, University of Frankfurt.  From 2000 to 2004 he was President of the German Phar ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by:

 

Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE