Researchers in Japan have discovered a new compound that may prove effective against drug-resistant hepatitis C virus (HCV)—as well as certain protozoan parasites and possibly other organisms. They recently reported their findings in PNAS Plus.
Relatively new direct-acting antivirals (DAAs) cure more than 90% of patients with chronic HCV. But DAA-resistant HCV has already been reported, so now there’s a need for novel therapeutics with less likelihood of breakthrough drug-resistant viruses.
Down with SPP
For this investigation, the team of researchers didn’t test another DAA. Instead they focused on signal peptide peptidase (SPP), a host cell protein used to propagate HCV. They reasoned that if they could find an inhibitor of SPP, it would cut off HCV at the knees.
“Direct-acting antivirals have made tremendous progress in treating HCV,” said corresponding author Yoshiharu Matsuura, PhD, professor in the Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. “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.”
To find an SPP inhibitor, the researchers infected human liver cells with HCV and then applied a variety of antibodies to the infected cells to see which might prevent the virus from spreading. One compound, YO-01027, demonstrated the most suppression of HCV propagation.
“For HCV to propagate in a host cell, the proteins that make up the virus particle need to be cleaved into their mature form,” explained lead author Junki Hirano, graduate student in the Research Institute for Microbial Diseases. “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.”
In addition, no drug-resistant virus strains emerged, even after 15 passages of HCV with YO-01027.
“Moreover, combined treatment with SPP inhibitors and DAAs showed synergistic effects, suggesting that combination therapy with SPP inhibitors and DAAs might be an effective treatment for patients with chronic hepatitis C, with a low frequency of emergence of drug-resistant viruses,” the authors wrote.
To determine the chemical structure of YO-01027, the researchers used a combination of computer simulations and in vitro tests to identify it as a dibenzoazepine. With this information, they may now be able to modify YO-01027 and other dibenzoazepine-containing drugs into novel therapies for not only drug-resistant HCV, but for some parasites, too.
Because the SPP gene is also encoded in protozoa, the researchers performed additional tests of YO-01027 against these parasites and found the SPP inhibitor significantly suppressed their growth.
“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,” Dr. Matsuura said. “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,” he added.
This research was supported by the Program for Basic and Clinical Research on Hepatitis of the Japan Agency for Medical Research and Development and by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.