Using computational modelling, researchers from QBI and the Indian Institute of Science (IISc) show that certain drug combinations could be highly effective at preventing SARS-CoV-2 entering host cells.
The COVID-19 pandemic has triggered an enormous global effort to develop effective treatments for the disease. This has included efforts to develop drugs that could block entry of the SARS-CoV-2 virus into host cells.
Viruses always take advantage of the hosts own cellular mechanisms and SARS-CoV-2 is no exception, says Dr Pranesh Padmanabhan.
“SARS-CoV-2 entry into cells requires the activation of spike proteins on the virus surface by one of two classes of host proteases: the serine protease TMPRSS2 and cysteine proteases Cathepsin B/L.”
“These proteases are thought to work independently, allowing SARS-CoV-2 to enter into cells through two alternative, independent pathways.”
Because of this, drugs targeting the TMRPSS2 pathway and drugs targeting the Cathepsin B/L pathways are in clinical trials for COVID-19 treatment.
Two protease with the one stone
Of course, if you block one protease, then the spike protein could still be activated by the other protease. Ideally, you would need to block both proteases at once.
When designing any drug combination, it’s important to make sure that the drugs are not antagonistic – that is, that one drug doesn’t undermine the potency or effectiveness of the other. This is not easy to predict, especially when combining drugs that target different biological pathways.
Dr Padmanabhan and his colleagues made a computational model of SARS-CoV-2 entry via the two pathways and then simulated blocking each pathway, as well as both pathways at once, to see what effect this would have on viral entry.
According to their findings, targeting both the TMPRSS2 and the Cathepsin B/L pathways simultaneously would have an unexpected, but welcome, synergistic effect.
“The synergy here arises because blocking any one entry pathway keeps the other open and allows virus entry, but blocking both pathways simultaneously shuts all entry pathways and protects cells,” says Prof Narendra Dixit, of IISc.
“Synergy between drugs implies that their combined effect is more than their individual effects added together,” he adds.
“Synergistic drug combinations are preferable because they allow the realization of the desired efficacy with lower net drug exposure, thus reducing toxicity,” says Dr Rajat Desikan, of IISc.
Dr Padmanabhan and his colleagues re-analysed published studies in the scientific literature relating to SARS-CoV, which is a close relative of SARS-CoV-2.
They found that when drugs targeting both protease pathways were combined, entry of SARS-CoV and of SARS-CoV-2 into cells was fully blocked.
“Drug synergy is evident in these experiments, validating our model predictions.”
They also analysed available data and found a lot of variability in the activity of these protease pathways across cell lines.
This raises the possibility that SARS-CoV-2 is more likely to be activated via the TMPRSS2 pathway in one tissue, but activated via the Cathepsin B/L pathway in a different tissue.
“Given the potentially broad tissue invasion of SARS-CoV-2, extending beyond the lungs, targeting both pathways may be important and synergistic in vivo,” says Dr Padmanabhan.
These findings are likely to apply beyond SARS-CoV-2, he adds.
“Entry of several other viruses — including other coronaviruses such as SARS-CoV, MERS-CoV, and influenza viruses — also occurs via the same two independent pathways.”
This research was a result of an international collaboration between the Indian Institute of Science and the Queensland Brain Institute and was published in PLOS Computational Biology.
