COVID-19 Breakthrough: Scientists Identify Possible “Achilles’ Heel” of SARS-CoV-2 Virus - SciTechDaily

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.

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.

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 Dikic, 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.

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.

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.

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.

Reference: “Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity” by Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Paul P.

July 29, 2020

July 28, 2020