Comprehensive protein interaction network helps discover candidate drugs for the treatment of COVID-19
Treatment options for COVID-19 remain limited. Researchers at the University of Helsinki and the University of Eastern Finland first searched for appropriate drug targets and reusable drugs and finally discovered six candidates with antiviral effects against SARS-CoV-2.
Understanding viral pathogenesis at the molecular level is key to the development of effective therapies for COVID-19. The virus does not have its own metabolism, but depends on the host, and the fact hinders the discovery of drugs.
SARS-CoV-2 infection dramatically alters the environment within host cells, enabling viral replication and transmission. However, relatively little is known about how these viral proteins interact with cytokines and host pathways.
'To effectively find drugs that can alter viral replication, we need to know which human proteins and viral proteins interact and how. Therefore, a comprehensive virus-host protein interaction network will help us identify potential protein targets for screening reusable drugs,' said Markku Varjosalo, director of research at the University of Helsinki (HiLIFE Institute of Biotechnology).
Researchers at the University of Helsinki (Institute for Biotechnology, Institute for Molecular Medicine, Finland) and the University of Eastern Finland used modern technology, proteomics, and chemoinformatics in combination with high-throughput screening during drug discovery to solve this task.
To effectively search for drugs that can alter viral replication, they first comprehensively mapped the physical, functional, and transient interactions formed by viral proteins with human host cells. Using the MAC-tag system developed by Varjosalo's laboratory, all 29 viral genes (ORFs) and 18 host cell receptors/co-factors of SARS-CoV-2 were achieved.
This analysis identified hundreds of host proteins for viral replication, which were then used as rational resources for drug repurposing by virtual screening methods.
Varjosalo said: 'Reusing existing drug molecules is much faster than traditional strategies, rather than investing in new drugs because their applicability and safety have been established.'
The entire process resulted in the suggested repurposing of 59 compounds for 15 protein targets. In addition, six drug candidates demonstrated antiviral effects by in vitro drug screening assays.
Researchers have discovered a powerful drug candidate, methotrexate, which inhibits viral replication.
'The results suggest that the antiviral activity of methotrexate may be related to its role in inhibiting the interaction of certain RNA helicases with other key proteins,' Varjosalo explained.
In future studies, these six drug candidates may be used in animal tests, such as mice or primates.
'We have established a comprehensive network of virus-host protein interactions to identify candidate proteins that can be targets for drug repurposing. Preliminary results suggest that several drugs have potential antiviral effects, 'said Dr. Xiaonan Liu, a postdoctoral researcher in the Varjosalo group.
The research project of the covid-19 consortium, led by the University of Helsinki, received funding from the Academy of Finland. This funding is dedicated to research and drug development for the Covid-19 vaccine.