Highly effective treatments for hepatitis C virus (HCV) have become available in recent years, drug-resistant viral strains can still lead to treatment failure for a sizable proportion of patients. Now, in a recent study published in PNAS Plus, reported a class of chemicals that can combat resistant strains of the HCV, as well as parasites that cause malaria and toxoplasmosis.

Hepatitis C is caused by a highly infectious virus affecting millions across the globe and can lead to a variety of liver ailments. While the HCV can sometimes be fought off and cleared by the immune system during the first few months of acute infection, up to 80% of those with HCV develop a chronic infection. This can lead to serious liver illnesses, including inflammation, cirrhosis, and hepatocellular carcinoma.

A team of researchers centered at Osaka University infected human liver cells with HCV. Later they treated the infected cells with different drugs to see which compound might prevent the virus from spreading. One compound, innocuously named YO- 01027, stood out above the rest.

"For HCV to propagate in a host cell, the proteins that make up the virus particle need to be cleaved into their mature form," lead author Junki Hirano explained. "We tested several compounds we thought may inhibit this cleavage process, and found that YO-01027 prevents a key HCV protein from undergoing cleavage and maturation. We correspondingly found the drug is very effective at suppressing HCV infection."

Patients with HCV are currently given direct-acting antivirals, which directly target and disrupt HCV proteins themselves. The drug tested in this study, however, inhibits one of the host cell's proteins — signal peptide peptidase (SPP) — that HCV hijacks during an infection. Importantly, resistant strains of HCV did not emerge over time when the infected cells were treated with YO-01027. This may owe to the unique way the compound prevents the virus from maturing.

"Direct-acting antivirals have made tremendous progress in treating HCV," the corresponding author Yoshiharu Matsuura explained. "The difficulty is that HCV shows quite high genetic diversity, even within a single patient. Antivirals produce a strong selective pressure that can cause HCV strains with resistant forms of the target protein to spread. By inhibiting the host's own SPP protein, we can largely bypass this selection problem."

Through a combination of computer simulations and in vitro tests, the researchers identified the chemical signature of YO-01027 responsible for its effectiveness, a structure called dibenzoazepine. Hence the researchers may now be able to modify YO-01027 and other dibenzoazepine-containing drugs to develop novel therapies for drug-resistant HCV.

"Now that we know some of the key structural features that make YO-01027 effective at inhibiting SPP, we can start the chemical fine-tuning," Matsuura added. "Ultimately, the goal is to make highly selective drugs to combat pathogens that need SPP to survive and spread. This includes not only viruses like HCV, but also parasites such as Plasmodium falciparum and Toxoplasma gondii that are responsible for malaria and toxoplasmosis. The possible applications are very exciting."