18 June 2021
The development of COVID-19 drugs such as Gilead Sciences’ Veklury (remdesivir) has mostly focused on directly targeting the SARS-CoV-2 coronavirus. But scientists at the University of Cambridge are taking a different approach to treating the disease by looking at an infection response pathway in human cells.
The mechanism, called the “unfolded protein response” (UPR), is present in human cells infected with SARS-CoV-2, the Cambridge team found. Combining two drugs targeting different prongs of the pathway significantly inhibited viral replication in human lung cell cultures to near undetectable levels, according to results published in the journal PLOS Pathogens.
The findings could open the door to new antivirals that can fight COVID-19 and its emerging variants, as well as other viral infections, the researchers said. Similar drugs could also be developed for diseases such as pulmonary fibrosis, cancer and neurodegenerative disorders, which also involve UPR activation.
The study centers on UPR, which is controlled by three sensor molecules: IRE1alpha, ATF6 and PERK. It’s triggered as a compensatory cellular response when coronaviruses replicate rapidly and put host cells under stress.
By using different SARS-CoV-2 virus proteins, including the spike protein that’s being targeted by most COVID drugs and vaccines, the Cambridge team found that all three branches of UPR were significantly dialed up in response to infection of the novel coronavirus.
An inhibitor of one prong of the UPR pathway produced a modest but promising reduction in virus replication. So the team tested different combos of the inhibitors.
They found that simultaneous inhibition of the IRE1alpha and ATF6 pathways with two drugs, dubbed KIRA8 and Ceapin-A7, respectively, showed the greatest activity, reducing virus production in cell cultures and human lung cells by up to 99.5%, the researchers reported.
The Cambridge team believes the UPR pathway—especially the IRE1alpha and ATF6 branches—offers a new antiviral approach for fighting COVID. As some of the compounds used in the current study have already been extensively investigated in preclinical research focused on diseases such as neurodegenerative disorders, cancer and pulmonary fibrosis, they represent “a promising antiviral strategy that could rapidly progress into a clinical trial,” the researchers wrote in the study.
Despite the availability of antiviral treatments such as remdesivir, scientists continue to search for better COVID therapies. A collaboration between the Icahn School of Medicine at Mount Sinai and the University of California, San Francisco recently showed a multiple myeloma drug called plitidepsin from Spanish company PharmaMar was nearly 30 times more potent than remdesivir in lab dishes. The drug targets the human protein eEF1A, which interacts with SARS-CoV-2 during an infection.
Because the Cambridge team's approach targets a cellular response instead of the virus itself, it could substantially reduce the chances of producing escape mutants and could target coronavirus variants, the researchers said.
What’s more, UPR activation is also implicated in certain clinical manifestations of COVID. For example, UPR can cause endothelial dysfunction, which is associated with acute respiratory distress syndrome that’s present in many hospitalized COVID patients. Therefore, UPR inhibitors could have dual therapeutic effects of both viral inhibition and reduction of symptoms, the team suggested.
“We hope this discovery will enable the development a broad-spectrum antiviral drug, effective in treating infections with other viruses as well as SARS-CoV-2,” Nerea Irigoyen, the senior author of the study, said in a statement. “We’ve already found it has an effect on Zika virus too. It has the potential to have a huge impact.”Print
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