The Middle East Respiratory Syndrome (MERS) Coronavirus (MERS-CoV) was first discovered in 2012 and can cause severe or even fatal pneumonia. There is currently no effective treatment for MERS-CoV. In a new study, researchers from research institutes such as the University of Munich in Germany have discovered a cell recovery process called autophagy as a potential target against MERS-CoV. They report that autophagy-inducing substances, including certain drugs that have been approved for sale, can greatly reduce the replication rate of the virus. The relevant research results were recently published in the journal Nature Communications. The title of the paper is “SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection”.
Figure 1 SKP2 leads to K48-linked poly-ubiquitination and thus degradation of BECN1
MERS-CoV is another highly pathogenic coronavirus that appears after severe acute respiratory syndrome coronavirus (SARS-CoV). It has spread to many countries and regions around the world and has become another severe challenge that threatens the world’s public health security. The World Health Organization (WHO) reports that since its introduction in 2012, it has caused approximately 2,500 cases in a total of 27 countries, and about one-third of infections can cause death. Led by Dr. Marcel Müller of the Institute of Virology of the University of Munich and Dr. Theo Rein of the University of Munich Medical School, these researchers found that MERS-CoV can replicate efficiently only when it inhibits autophagy. Based on this initial discovery, they then identified substances that could induce autophagy and could be used to limit this viral infection.
“Autophagy” is a cell recovery process that enables cells to process damaged substances and waste while retaining intact components for integration into new cell structures. This autophagy degradation process also recognizes pathogen-derived components, such as viruses, which are considered waste and eliminated. Many viruses are known to have evolved strategies that abnormally regulate or inhibit autophagy. Therefore, Dr. Müller and colleagues set out to determine whether MERS-CoV can regulate autophagy degradation. First, under stringent biosecurity conditions, the researchers infected cells with MERS-CoV. Subsequent observations showed that the cell recovery process was disrupted in cells infected with the virus. Dr. Müller explained, “This result clearly shows that MERS-CoV benefits from the weakening of this cell recovery process.”
The researchers also successfully identified an unknown molecular switch that regulates this autophagy degradation process: the SKP2 protein. They found that MERS-CoV activates this molecular switch, which slows this recovery process in the cell and avoids degradation. Using these new insights, they treated cells infected with MERS-CoV with various SKP2 inhibitors to activate this autophagy degradation process. This strategy proved to be successful, as these autophagy-inducing substances reduced the virus replication by up to 28,000 times. Among these substances that cause this effect, there are some drugs approved for sale, such as niclosamide. Niclosamide is a drug used to kill roundworms and has been previously identified as an SKP2 inhibitor. Importantly, niclosamide has been shown to significantly reduce MERS-CoV virus replication in cell cultures.
Dr. Müller said, “Our results show that SKP2 is a promising starting point for the development of new substances that can fight MERS virus and even other autophagy-dependent viruses.” However, SKP2 inhibitors cannot directly target MERS virus. Therefore, Dr. Müller expects their use to reduce the risk of resistance. Dr. Müller said, “However, SKP2 inhibitors need to be tested in vivo before they are used as drugs. In addition, because even approved drugs can have side effects, the risks and benefits of their use in the body must be properly assessed.”
The researchers will also test whether SKP2 inhibitors might fight other coronaviruses, such as severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and the new coronavirus (2019-nCoV) currently raging in China.
1. Nils C. Gassen et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nature Communications, 2019, doi:10.1038/s41467-019-13659-4.
2. A new treatment strategy against MERS https://medicalxpress.com/news/2020-01-treatment-strategy-mers.html