Researchers from the Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Germany have shown that a long-forgotten molecule for antiviral therapy can actually help the human immune system fight viruses. Their study was published online (April 19th) in The EMBO Journal of the European Molecular Biology Organization.
When pathogens such as bacteria, parasites or viruses infect the cells of a living organism, the cells produce and release specific proteins, termed interferons. Interferons are used by cells as a way of communication to warn that there is danger in the neighborhood and to alert the immune system. For this reason, since the discovery of interferon in 1957 by Isaacs and Lindenmann, scientists are trying to develop and use substances that can induce the production of interferon (interferon inducers) and trigger an immune response against a variety of viruses. Krueger and Mayer successfully developed such a compound, 2,7-bis(2-diethylaminoethoxy)fluoren-9-one or tilorone. Several others tested acridine. But in 1976 Grunberg and colleagues developed 10-carboxymethyl-9-acridanone (CMA), the most promising interferon inducer at that time because it could protect mice against several viruses. Disappointingly, all of these compounds were abandoned because they could not protect humans.
But since scientists are persistent individuals, Ph.D. candidate Taner Cavlar and colleagues in the laboratory of Professor Veit Hornung, have had an idea which wanted to explore. They first found how CMA acts in the cell of a mouse and how it induces interferon. This is done by first binding to a receptor in the cell, a protein called STING.
Many mouse and human genes are 100% identical, others are conserved in various degrees or not at all. Some of these variations can be so important that they change the function of the protein. Mouse and human STING is such an example.
The researchers found the region on mouse STING which CMA binds to, like a key to its lock. They later saw that this particular region is different in human STING. Therefore, CMA cannot find its “lock” to initiate all cellular mechanisms that lead to interferon production. To confirm this, they created a chimeric STING, which contained most of the part of human STING in addition to the mouse STING region to which CMA binds, and they indeed caused production of interferon in human cells in culture.
This study has two important aspects. In a more general view, it shows why studies on mice do not always reflect on humans and directs scientists to look at differences/dissimilarities in the protein sequence between mice and humans that change protein function. Recently, another study argued that mice are not a good model system to study human immunological diseases. Maybe the Cavlar study shows that if scientists focused on identifying the variations that lead to failure, new drug candidates, that have initially failed, could re-enter clinical trials after some optimization. “This is an example of the fact that results from animal models cannot always be easily transferred to humans. Comparative investigations on human cells should take place at an early stage of active substance development.” said Professor Hornung.
Lastly, now that scientists know the structure of STRING, as shown by the Cavlar study, they can develop modified CMA or new interferon inducers in the human body. That still requires years of hard work. “Nevertheless, when we are able to develop such a potent substance, only very small amounts would be enough to fight a variety of viral infections early on,” said Professor Hornung.