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 (Nature, DOI 10.1038/s41586-020-2601-5).
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.”
Professor Ivan Đikić
Director of the Institute of Biochemistry II of University Hospital Frankfurt and
Group Leader at the Buchmann Institute for Molecular Life Sciences at Goethe University and
Max Planck Fellow at Max Planck Institute of Biophysics, Frankfurt
, Tel.: +49 (0)69 6301-5964, email: firstname.lastname@example.org, Twitter: @iDikic2
Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Huib Ovaa, Brenda Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek, Ivan Dikic. Inhibition of papain-like protease PLpro blocks 1 SARS-CoV-2 spread and 2 promotes anti-viral immunity. Nature, DOI 10.1038/s41586-020-2601-5, https://www.nature.com/articles/s41586-020-2601-5
Markus Bernards | idw - Informationsdienst Wissenschaft
Bayreuth physicists discover mechanism for the formation of blood platelets
28.07.2020 | Universität Bayreuth
Digitizing chemistry with a smart stir bar
24.07.2020 | American Chemical Society
Although no life has been detected on the Martian surface, a new study from astrophysicist and research scientist at the Center for Space Science at NYU Abu...
New approach creates synthetic layered magnets with unprecedented level of control over their magnetic properties
The magnetic properties of a chromium halide can be tuned by manipulating the non-magnetic atoms in the material, a team, led by Boston College researchers,...
Scientists of Tomsk Polytechnic University jointly with a team of the V.E. Zuev Institute of Atmospheric Optics of the Siberian Branch of the Russian Academy of Sciences have discovered a method to increase the operation range of optical traps also known
Optical tweezers are a device which uses a laser beam to move micron-sized objects such as living cells, proteins, and molecules. In 2018, the American...
An international team led by researchers at Princeton University has uncovered a new class of magnet that exhibits novel quantum effects that extend to room...
International team of scientists with Mainz participation proposes plans for high-intensity gamma radiation source at CERN
The ‘Gamma Factory initiative’ – an international team of scientists – is currently exploring a novel research tool: They propose to develop a source of...
23.07.2020 | Event News
21.07.2020 | Event News
07.07.2020 | Event News
28.07.2020 | Earth Sciences
28.07.2020 | Health and Medicine
28.07.2020 | Life Sciences