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).
Repurposing existing drug molecules is faster
The researchers at the University of Helsinki (Institute of Biotechnology, Institute for Molecular Medicine Finland) and the University of Eastern Finland 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.
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.
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,” explains Varjosalo.
The next step – Animal testing?
The six candidate drugs could be taken into animal testing, such as mice or primates, in a future study.
“We built a comprehensive virus–host protein interaction network to identify protein candidates that can be used as targets for drug repurposing. The preliminary results suggested several drugs with potential anti-viral effects,” said Dr Xiaonan Liu, a postdoctoral researcher in the Varjosalo group.
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