Treatment options for COVID-19 remain limited. Researchers at the University of Helsinki and the University of Eastern Finland first searched for suitable drug targets and repurposable drugs for these, leading to finding six candidate drugs that demonstrate antiviral effects against SARS-CoV-2.
Understanding viral pathogenesis at the molecular level is critical in developing effective therapies for COVID-19. Drug discovery is hindered by the fact that viruses do not have their own metabolism, but are dependent on the host.
SARS-CoV-2 infection dramatically alters the intracellular environment of host cells to both enable virus replication and spread. However, relatively little is understood about how these viral proteins interact with the cellular factors and the host pathways involved.
“To effectively search for drugs that could modify viral replication, we need to know which human proteins and viral proteins interact and how. Thus, a comprehensive virus–host protein interaction network will help us to identify the potential protein targets for screening repurposable drugs,” says Markku Varjosalo, Research Director at the University of Helsinki (Institute of Biotechnology, HiLIFE).
“Instead of merely repurposing drugs that are currently in use, our idea was also to look at drugs that are no longer in use, as well as drugs that are still in development,” says Professor Antti Poso from the School of Pharmacy and the Drug Discovery and Delivery Research Community at the University of Eastern Finland.
Repurposing existing drug molecules is faster
The researchers at the University of Helsinki (Institute of Biotechnology, Finnish Institute of Molecular Medicine) and the University of Eastern Finland (School of Pharmacy) tackled the task using a combination of modern technologies, proteomics and cheminformatics with a high-throughput screening in the drug discovery process.
To effectively search for drugs that could modify viral replication, they first comprehensively mapped the physical, functional and transient interactions that the viral proteins form with the human host cells. This was achieved by utilising the MAC-tag system developed by Varjosalo Lab, on all the 29 viral genes (ORFs) and 18 host cell receptors/co-factors of SARS-CoV-2, as well as a novel, computer-assisted screening method for drug discovery, developed by Poso’s research group.
The analysis pinpointed hundreds of host proteins used for viral replication, which then served as a rational resource for drug repurposing via a virtual screening approach.
“Rather than investing in new drugs, repurposing existing drug molecules is considerably faster than traditional strategies, since their applicability and safety has already been established,” Varjosalo says.
According to Poso, it would have been almost impossible to achieve these results just a couple of years ago.
“Modern supercomputers, skills to use the opportunities provided by them, and seamless collaboration between the groups involved in the study have played a crucial role in this.”
The research suggested repurposing 59 compounds for 15 protein targets
The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets.
Furthermore, six candidate drugs demonstrated antiviral effects using an in vitro drug-screening assay.
The researchers identified a strong candidate drug, methotrexate, which can inhibit viral replication.
“The results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on suppressing certain RNA helicase interactions with other key proteins.”
The six candidate drugs could be taken into animal testing, such as mice or primates, in a future study.
The research project of the CoVIDD consortium, led by the University of Helsinki, has received funding from the Academy of Finland. This funding is aimed specifically at research into Covid-19 vaccines and pharmaceutical development.
Original article: Xiaonan Liu, Sini Huuskonen, Tuomo Laitinen, Taras Redchuk, Mariia Bogacheva, Kari Salokas, Ina Pöhner, Tiina Öhman, Arun Kumar Tonduru, Antti Hassinen, Lisa Gawriyski, Salla Keskitalo, Maria K Vartiainen, Vilja Pietiäinen, Antti Poso, Markku Varjosalo. SARS-CoV-2–host proteome interactions for antiviral drug discovery. Molecular Systems Biology, 2021. DOI: 10.15252/msb.202110396
For further information, please contact:
Antti Poso, Professor, tel. +358 40 355 2462, antti.poso (a) uef.fi
University of Eastern Finland, School of Pharmacy
DrugTech Research Community
Research Group: Molecular Modeling and Drug Design
Markku Varjosalo, Research Director, tel. +358 50 318 5015, markku.varjosalo (a) helsinki.fi
Institute of Biotechnology, HiLIFE – Helsinki Institute of Life Science, University of Helsinki
Research Group: Molecular systems biology