LONDON – The discovery of a compound that can prevent replication of various coronaviruses – which cause common respiratory infections as well as rare but highly dangerous infections – has raised hopes that it may be possible in the future to develop drugs to treat these infections.
Although most coronaviruses circulating in people cause self-limiting respiratory infections, there have been recent outbreaks of deadly viral illness caused by the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV).
Currently, no approved drugs exist to treat any coronavirus infection. Effective drugs would be highly desirable, however, not just for the common respiratory infections but, more importantly, to have available in the event of future pandemics caused by SARS-CoV, MERS-CoV or related viruses, which are present in animal reservoirs and could enter and/or spread in the human population at any time.
A study carried out by an international European team of researchers has now found that a compound named K22 can inhibit the replication of coronaviruses, including SARS-CoV and MERS-CoV. The team, led by Edward Trybala of the University of Gothenburg in Sweden and Volker Thiel of the University of Berne in Switzerland, reported their findings in the May 29, 2014, issue of PLOS Pathogens, in a paper, titled "Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus."
Trybala, who is associate professor in the department of clinical virology at the University of Gothenburg, told BioWorld Today: "Although it will be a long time before the compound we have identified could be developed into a drug, this discovery is important because there are currently no drugs to treat these coronaviruses, which have the potential to cause pandemics. We emphasized this in our paper, which states that because of past outbreaks of SARS and MERS, it is important to invest significant efforts in developing new drugs to allow us to combat coronavirus infections.
"Our studies will also help us to identify new antiviral targets that are druggable," he added.
The team currently is working on optimizing the compound identified. "We are screening analogue compounds of K22 to try to find compounds with improved activity," Trybala explained. "We are also looking for an animal model that will allow us to test the activity of these compounds in vivo."
As part of their search for compounds that could be good candidate drugs to treat coronavirus infections, Trybala, Thiel and their collaborators screened almost 17,000 compounds for antiviral activity against one of the most common circulating human coronaviruses, which is called HCoV-229E. K22 and a compound with a similar structure, J15, were among the handful of compounds that delivered promising results.
In further investigations, the team probed the effect of K22 on the viral replication cycle in cultures of susceptible human cells. When coronavirus infects cells, it manufactures more than 20 proteins. Some of those target membranes within the host cell, modifying them in order to produce a membranous replication center, where viral enzymes and other proteins form a complex that synthesizes viral RNA, which is required for production of viral structural components and assembly of thousands of progeny virions.
The scientists showed that the activity of K22 is associated with a viral nonstructural protein called Nsp6, which spans the host cell membrane six times.
"This protein is believed to be involved in the production of the replication center," Trybala said. "We think it modifies the host cell membranes and serves as an attachment for the rest of the viral replication complex."
To prove the key role of Nsp6, the team genetically modified coronaviruses by introducing specific mutations into part of a viral gene that encodes Nsp6. Those viruses were resistant to K22. Trybala added: "Although we did not perform direct protein-binding experiments to look at the interaction between K22 and Nsp6, our genetic experiments allow us to conclude that K22 does affect the function of Nsp6, because mutations in Nsp6 are required in order to produce escape mutants that are resistant to the drug."
Writing in PLOS Pathogens, the authors concluded that the "remarkable efficacy of K22-mediated inhibition of coronavirus replication confirms that the employment of host cell membranes for viral RNA synthesis is a crucial step in the coronavirus life cycle and, importantly, demonstrates that this step is extremely vulnerable and also druggable for antiviral intervention."