Using a high-throughput strategy to search for therapeutic options to combat the Chikungunya virus, researchers have identified several previously approved drugs, as well as a novel class of inhibitors, as potential antiviral agents.
Chikungunya virus (CHIKV) is a mosquito-borne pathogen which is endemic to parts of tropical Africa, but has extended its range in recent years to become a potentially global threat. It is now found in Asia and has reached the Americas. A few regional outbreaks have also been reported in Southern Europe. It is transmitted to humans by the mosquitos Aedesaegypti and A. albopictus, and normally causes flu-like symptoms which can, however, persist for months and may in rare cases result in death. However, patients who recover from the acute phase often go on to develop chronic and debilitating joint pain. There is currently no vaccine available and no antiviral drugs have been shown to be effective against it. Now, an international research collaboration, including LMU medicinal chemist Franz Bracher, has used a high-throughput strategy to find vulnerable targets in the pathogen’s replication cycle. In addition, they show that a number of drugs already in use for other purposes have antiviral effects in a mouse model of Chikungunya infection. The results, which appear in the journal Nature Communications demonstrate the efficacy of an integrated strategy for the comprehensive discovery of proteins that promote viral replication and the rapid identification of pharmacological agents that interfere with their function.
As obligate intracellular pathogens, all viruses require specific host proteins for their replication. This prompted researchers led by Thomas F. Meyer (Max Planck Institute for Infection Biology, Berlin) to carry out a genome-wide screen for host proteins that are essential for the virus’s ability to reproduce in human cells. To do so, they used an automated procedure to individually knock out each human gene in turn. They then infected all the clones with the virus and subsequently analyzed the numbers of virus particles produced by each. Since the gene targeted in each clone is known, they were able to identify 100 host proteins that are essential for virus replication.Based on existing knowledge for each of these genes, they were able to pinpoint the functional pathways in which each is involved, and thus identify the processes necessary for viral infection. In cooperation with virologists led by Marc Lecuitat the Institut Pasteur in Paris and groups at the Charité Hospital and the Steinbeis Innovation Center in Berlin, the Institute of Technology in Tartu, Estonia, and Bracher’s team at LMU’s Department of Pharmacy, they then set out to identify drugs that interacted with these proteins and investigated whether they also inhibited the replication of CHIKV. A number of agents targeting different cellular processes were found to effectively prevent the production of new virus particles. “Among those that did so were drugs that are already used for other indications, but had not previously been considered for use in the treatment of viral infections, as well as novel types of low-molecular-weight compounds, such as inhibitors of the protein kinase CLK1, which were synthesized in our laboratory,” Bracher explains.
One particularly encouraging aspect of the work is that, as the researchers report, preliminary results suggest that this strategy is also applicable to other pathogenic viruses. “This innovative approach makes it possible to screen infectious pathogens for susceptibility to well characterized drugs that are already being used to treat other conditions, which can then be made available relatively swiftly to combat outbreaks of infections,” says Bracher. “On the other hand, as in the case of our kinase inhibitors, it can also lead to the identification of entirely new classes of substances as potential antiviral agents.”
Nature Communications 2016