Researchers at the University of Helsinki and the University of Eastern Finland first searched for suitable drug targets and repurposable drugs for treatment options for COVID-19.
They found six candidate drugs that demonstrate antiviral effects against SARS-CoV-2.
“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 used 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.
Identified a strong candidate drug
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
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.