Blocking the Entrance

Entry inhibitors usher in a new phase of hep C research
by Larry Buhl

Dr. Susan Uprichard
Future therapy for hepatitis C infection may include a variety of drugs working together to target the virus at multiple stages of its life cycle, according to a research team at the University of Illinois at Chicago College of Medicine, which has found a promising new way to combat the virus with a drug that already exists.

The researchers, who have published their findings in the journal Nature Medicine, suspected that a molecule embedded in the membrane of human liver cells that aids in cholesterol absorption might also allow entry of the hepatitis C virus (HCV), the first step in hepatitis C infection.

The UIC researchers tested whether the receptor called NPC1L1, known to help maintain cholesterol balance might also be transporting the virus into the cell. NPC1L1 is common in the gut of many species, but found on liver cells only in humans and chimpanzees. These primates are the only animals that can be infected with HCV.

The team, led by Susan Uprichard, assistant professor in medicine and microbiology and immunology at UIC, wanted to find out whether knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.

Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said because the receptor is involved in cholesterol metabolism it was already well-studied. A drug that specifically and uniquely targets NPC1L1 already exists and is approved for use to lower cholesterol levels, but not for treating hepatitis C—at least not yet, he told A&U.

The FDA-approved drug ezetimibe (sold under the trade name Zetia) is available now and perfectly targeted to the receptor. This gave the researchers an ideal method for testing NPC1L1’s involvement in HCV infection, according to Sainz.

“In the first step, the cell culture test, we looked at different ways of blocking the virus, using RNA interference to ‘silence the messenger’ and antibody blocking to bind to the receptor,” Sainz said. “But we found that the ezetimibe was most effective in blocking the receptor.”

The next step was to use a small-animal model, by injecting human liver cells into mice to repopulate the liver—essentially replacing mouse liver cells with human liver cells. The team used ezetimibe to block the receptor before, during and after inoculation with the virus, and then evaluated the receptor’s role in infection and the drug’s potential as an anti-hepatitis agent.

The researchers found that, unlike any currently available drugs used to treat HCV, ezetimibe was able to inhibit infection by all six types of the hepatitis C virus.

The study opens up a number of possibilities for therapeutics, according to Sainz. “The hypothesis is that ezetimibe, which is used now to lower a patient’s cholesterol, could also be used in a synergistic way with hepatitis C drugs to treat the virus,” he told A&U.

Sainz explains that the drug could be used in several ways. First as a prophylactic: “Because ezetimibe is an entry inhibitor, there is the possibility of giving this drug to people at high risk of contracting HCV; people exposed to the virus in healthcare settings, or IV drug users.” That pool of people is relatively small, Sainz admits. For the vast majority of people carrying the hepatitis C virus, ezetimibe could make current regimens more effective in treating HCV. Because it prevents entry of the virus into cells, ezetimibe may help protect the virus-free liver cells from infection.

“Like HIV therapy, you could see a cocktail targeting the virus at different stages in the life cycle. The virus wants to spread to cells that have already been cleared. Ezetimibe could stop the spread and stop the reinfection of those cells, in theory.” Ezetimibe would not replace the new protease inhibitors, which were released last year to treat HCV, but rather work with them. It could, however, eliminate the need for other treatments, such as interferon, which has well-known debilitating side effects, Sainz says.

Uprichard said that ezetimibe is quite safe and has been used long-term without harm by people to control their cholesterol.

The next step, Sainz says, is a human trial using ezetimibe. He says the data of that trial should be available this year.

Larry Buhl is a freelance journalist and screenwriter living in Los Angeles.

February 2012