An international study led by researchers at Monash University's Biomedicine Discovery Institute (BDI) in Melbourne has shown how the hepatitis C virus (HCV) takes over the communication systems in infected host cells, revealing potential new therapeutic targets for HCV and other diseases.

Affecting about 2 percent of the world's population, HCV infection can lead to chronic hepatitis, which may then progress to liver cirrhosis and hepatocellular carcinoma.

The introduction of several direct-acting agents such as protease or RNA polymerase inhibitors has revolutionized HCV therapy and led to a sustained virological response in most treated patients. However, the failure of those agents and resistance in some patients remains an important challenge.

"Despite the high rates of virological cure achieved with these treatments, the infection is not eliminated in 1 [percent] to 15 percent [of patients], depending on the patient group and regimen," lead researcher Christian Doerig, a professor with the Department of Microbiology at Monash BDI, told BioWorld Today. "This incidence is likely to increase with time and with sustained treatment pressure on the virus."

Importantly, the approach used in the Monash study, which identified a molecule that prevented HCV replication within cells, may have broader application to other infectious diseases, since all intracellular pathogens rely on their host cell signaling system to replicate.

The study, published in the May 8, 2017, online edition of Nature Communications, focused on protein kinases, building on previous work on malaria by Doerig, which had established that chemical inhibitors of some of the host cell protein kinases killed malarial parasites.

While that earlier work has yet to result in any new antimalarial drugs, "we have unpublished data showing that a kinase inhibitor that has been developed and approved for the clinical treatment of cancer has exquisite in vitro antimalarial properties in cultured malaria parasites, which is very encouraging," noted Doerig.

The Monash BDI researchers collaborated with Canadian-based company Kinexus Bioinformatics, using an antibody microarray developed by that company, to screen for factors involved in cell signaling that were modulated by HCV replication, including protein kinases.

"This antibody microarray allowed us to find a number of new cell signaling pathways that were activated or suppressed by HCV infection," said study first author Gholamreza Haqshenas, a senior research fellow in Doerig's laboratory.

"We found about 100 signaling molecules from the host cell to be affected by HCV infection, with pathway analysis implicating components of the JAK/STAT, NF-kB, and MAPK/JNK pathways," Haqshenas told BioWorld Today.

"This is an important finding, because we now have a repertoire of potential host-encoded targets for novel drug discovery investigations," Doerig added.

Haqshenas explained how the researchers used gene-silencing technology to determine whether the host cell factors identified by the antibody array were important for HCV replication and therefore potential targets for anti-HCV compounds.

They then used a recently discovered small molecule to selectively block the activity of the enzyme mitogen-activated protein kinase (MAP4K2). MAP4K2 was one of the enzymes that microarray analysis and shown to be modulated by infection, while gene silencing with small interfering RNA (siRNA) had demonstrated its importance in viral replication.

The researchers then showed that when the new molecule was introduced into host cells that were then infected with HCV, the host cells showed no apparent adverse effects but no longer supported viral replication.

"We treated hepatocytes with the kinase inhibitor, infected them with HCV, then assessed viral replication by measuring expression of nonstructural protein 5A [NS5A], which plays a key role in HCV replication," said Haqshenas.

Doerig said that his group's new study provided a compelling "proof of concept" and that "the platform we have established can be adopted to identify new anti-infective compounds against any pathogen, including viruses, bacteria and parasites that invade mammalian cells."

Importantly, "fighting a pathogen by hitting an enzyme from the host cell is likely to slow the emergence of drug resistance, because the pathogen cannot easily escape through the selection of target mutations," he added.

"We identified a number of host cell signaling enzymes that are modulated by HCV infection, while siRNA analysis of the genes shown to be modulated by infection told us which of these genes were required for successful infection.

"We thereby identified a number of potential targets for new drugs, and showed that a drug-like small-molecule inhibitor of one of these impaired viral replication. Since it is becoming increasingly apparent that all intracellular pathogens require host cell signaling components, this principle can be applied to identify targets for many infectious diseases," said Doerig.

"Many tropical diseases are caused by intracellular pathogens, so by implementing this strategy we hope to find new drug targets for such neglected diseases among human kinases, which are major targets for diseases with a high market potential, such as cancer.

"This strategy might lead to repurposing some of the drugs developed for cancer; of particular interest would be drugs that fail the late stages of clinical trials or [show] lack of efficacy in their original indication, which could rapidly undergo clinical trials against infectious diseases," he said.

Meanwhile, in the immediate future, the Monash researchers will extend their research to include studies on other infections such as the Zika virus and toxoplasmosis.