Targeting autophagy to treat MERS coronavirus

Targeting autophagy to treat MERS coronavirus

The MERS coronavirus discovered in 2012 can cause severe pneumonia, which is often fatal. So far there is no effective therapy. Scientists have now identified a cell-specific recycling mechanism, autophagy, as a new target for combating the virus. Active ingredients that promote autophagy, including approved drugs, have been able to greatly reduce the multiplication of the virus in cells. The work was published in the journal Nature Communications.

There are around 2,500 MERS cases have been reported to the World Health Organization in 27 countries; about a third of those infected died. The authors have now discovered that the MERS virus has to slow down the cellular process of autophagy in order to multiply. On the basis of this knowledge, the team identified active ingredients that boost autophagy and thus significantly inhibit virus growth in the cells.

Autophagy is a body's own recycling mechanism that cells use to break down damaged material and waste products. The remaining building blocks are then available again for the construction of new cell structures. Components of pathogens such as viruses are also recognized and disposed of as waste products through this process of "self-digestion". 
A number of viruses have developed various strategies to avoid degradation. The team  examined whether the MERS virus also influences the autophagy mechanism. To this end, the scientists infected cells with the pathogen under the highest safety precautions. In fact, they could see that the recycling process in MERS-infected cells was disrupted. "This result was a clear indication that the MERS pathogen benefits from a weakening of cellular recycling," explains the author.

The research team also succeeded in identifying a previously unknown molecular switch that regulates the course of autophagy: the SKP2 protein. As the scientists found, the MERS virus activates this molecular switch in order to throttle the recycling machinery and thus avoid its own degradation. The working group used these findings. They treated MERS-infected cells with various SKP2 inhibitors to stimulate the disposal process. The strategy was successful: the autophagy-inhibiting agents reduced the virus multiplication by up to 28,000 times. Among the substances tested were already approved substances, such as the niclosamide used against tapeworm diseases, which was also identified as an SKP2 inhibitor. 

"Our results show that SKP2 is a promising starting point for the development of new active substances against the MERS virus - and possibly also against other autophagy-dependent viruses", explains the author. Since SKP2 inhibitors do not attack the virus directly, the authors expect a lower risk of developing resistance when used. "However, tests for the use of SKP2 inhibitors as medication are still missing in the organism. In addition, a clear risk-benefit assessment is necessary, since already approved medication can have side effects," says the virologist. In addition, the scientists will test whether SKP2 inhibitors are also active against related coronaviruses such as the SARS virus or the virus that is currently circulating in China (2019-nCoV).