Nature Medicine | Spoonful of Medicine

Drug target suggested for MERS as case count rises

Cluster of vesicles made by virus from usurped and reshaped membranes.

Cluster of vesicles made by virus from usurped and reshaped membranes.

Volker Thiel, Edward Trybala and colleagues

Since its appearance in Saudi Arabia in 2012, Middle Eastern Respiratory Syndrome (MERS) has spread to fifteen countries, including the US, where two cases were confirmed in the past month. Worryingly, about 30% of confirmed cases have been fatal, and the lack of specific antiviral drugs for the MERS-coronavirus (MERS-CoV), which causes the illness, poses a threat to public health.

A new insight could help pave the way to treatments in the future for this type of virus. In a paper published today in Plos Pathogens, clinical virologist Edward Trybala and his colleagues at the University of Gothenburg in Sweden describe a compound called K22 that inhibits coronavirus growth in human cells.

Trybala’s initial goal was to identify drug candidates that inhibit common coronaviruses, such as respiratory syncytial virus, for which there are currently no drugs. In a screen of over 15,000 compounds, K22 stood out for its ability to selectively block a common human coronavirus from reproducing in cultured human lung cells. He then approached Volker Thiel, a virologist from the University of Bern in Switzerland, who studies how host cells interact with coronaviruses. Thiel’s lab produced a recombinant version of the Severe Acute Respiratory Syndrome coronavirus, SARS-CoV, which caused over 700 deaths during an outbreak in 2003 and 2004, and they found that K22 moderately inhibited SARS-CoV replication.

“We were ready to submit our work and then MERS came,” Thiel says, referring to the recent MERS outbreak that began in Saudi Arabia in 2012. They tested K22 on MERS-CoV in cultured human airway epithelial cells—the cells naturally targeted by coronaviruses, and found that it blocked MERS-CoV with even better efficacy than SARS-CoV. K22 also inhibited several more human and animal coronaviruses. This means that its mechanism of action is conserved across the coronavirus species. “It’s clear that there is a new drugable target,” says Thiel.

“I think this is a terrific concept,” says Mark Denison, a pediatric infectious disease specialist who studies coronaviruses at Vanderbilt University School of Medicine in Nashville, Tennessee. “It demonstrates that you can target very highly conserved processes.”

Replication blocker

K22 blocks a critical step in viral replication in which the virus hijacks some of the cells own membranes to build structures called double membrane vesicles (DMVs). The compound hampers the formation of these structures, thus preventing the virus from copying its genome and replicating inside the cell. Although the precise target of K22 is still unknown, there is some evidence that it binds to the viral protein nsp6, which is involved in altering host cell membranes to make DMVs.

Matthew Frieman, a virologist at the University of Maryland School of Medicine in Baltimore, says that a broadly inhibiting antiviral drug like K22 would be particularly effective, but points out that despite the success of many coronavirus antiviral drugs in cell culture, few have worked in animal models. Frieman’s group recently published the results of a screen that tested 290 drugs approved by the US Food and Drug Administration for antiviral activity against MERS-CoV, and is currently testing positive hits in animal models.

According the Thiel and Frieman, the biggest roadblocks to moving coronavirus antiviral research forward are lack of interest and funding. Perhaps the recent dramatic increase in the number of MERS cases will stir up some of both.


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