New strategy against coronaviruses

Five years have passed since the coronavirus pandemic began. Although biomedical research has delivered groundbreaking vaccines and treatments in record time, coronaviruses remain a global threat. Not everyone can be vaccinated, and for high-risk patients, infection with the virus can still be serious or even fatal. Coronaviruses can mutate rapidly and overcome the effectiveness of vaccines or drugs. New antiviral agents are therefore urgently needed to counter potential future coronavirus outbreaks.

A team led by PD Dr Evangelos Karousis from the Department of Chemistry, Biochemistry and Pharmaceutical Sciences at the University of Bern has now gained new insights into Nsp1 protein (non-structural protein 1) of coronaviruses which is central to infections. These findings point the way to the targeted development of broad-spectrum antiviral therapies against coronaviruses. The research team is part of the National Centre of Competence in Research NCCR RNA & Disease of the Swiss National Science Foundation, for which the University of Bern is Leading House and ETH Zurich is Co-Leading House. The study is supported by the Multidisciplinary Centre for Infectious Diseases (MCID) at the University of Bern. The research results were recently published in the scientific journal Cell Reports.

Two mechanisms for controlling the host cell

Nsp1 is one of the first viral proteins to be produced in the human cell during infection by coronaviruses such as SARS-CoV-2 and MERS-CoV. Earlier studies within the framework of the NCCR RNA & Disease and in collaboration with the group of Prof Nenad Ban from the ETH Zurich and the group of Prof Dr Volker Thiel from the Institute of Virology and Immunology at the Vetsuisse Faculty of the University of Bern had already shown that a key function of Nsp1 is to manipulate the host cell such that it produces more viral proteins than the cell's own proteins. "Nsp1 achieves this by two mechanisms: on the one hand by inhibiting the production of the cell's own proteins, and on the other hand by the targeted destruction of the cell's own mRNA, which contains the blueprints for vital host proteins," summarizes Evangelos Karousis, last author of the study. However, it was unclear until now whether these two mechanisms are interconnected or can occur separately.

Independent functions of Nsp1

The present study shows that Nsp1 must bind to ribosomes to fulfil both functions. However, degrading the cell's own mRNA does not require protein synthesis inhibition. "By decoupling the different functions of Nsp1, we gain new insights into the basic mechanisms by which coronaviruses suppress host cell protein production," explains Karousis. The researchers also compared whether the functions of the Nsp1 protein differ between SARS and MERS coronaviruses. "Surprisingly, we found that Nsp1 from MERS-CoV only inhibits protein production, but does not trigger the destruction of mRNA," says Emilie Bäumlin, first author of the publication and former Master student of the interdisciplinary Master program "Molecular Life Sciences" at the University of Bern. The mechanism of destroying the host's own mRNA is therefore not common to all species of coronaviruses. The study thus suggests that drug development should focus on the binding of Nsp1 to human ribosomes rather than on the degradation of mRNA.

In their experimental system developed at the University of Bern, the researchers tested whether certain known drugs such as Amentantrone and Montelukast could inhibit Nsp1. "We were unable to demonstrate any inhibition of Nsp1 functions with either drug though," says Karousis. Further research is needed to identify molecules that could specifically block the interaction of Nsp1 with ribosomes and thus interrupt the virus's control over human cells.

A step towards antiviral pan-coronavirus therapies

The findings will help to prioritize more targeted strategies for the development of antiviral agents. “Nsp1 is unique to coronaviruses and has no equivalent protein in humans. It plays a crucial role in the replication of the virus; it is active early in the infection process and moreover well researched. Altogether, this makes Nsp1 a promising target for broadly effective antiviral drugs that could stop infections at an early stage," concludes Karousis.