Once HCV enters a liver cell, its genes guide the production of proteins that will become the
inner core and surface coat of new viral units. First of all, the HCV makes an immature protein--a
kind of unfinished sheet of material, which the Hep C protease cuts into the finished proteins, which then become the virus's outer cloak.
Scientists have developed protease inhibitors, which stick to protease and stop its scissor-like
function. These drugs have been used in the treatment of HIV for years, and hopefully they will be valuable in Hep C treatment as well (
).
Boerhinger Ingleheim reports the initiation of Phase I trials of their HCV protease inhibitor, BILN 2061. “Boerhinger PI is the first to go into humans … none of the other PI programs are that far developed.” (AASLD Conference: New Therapeutic Strategies for Hepatitis C, Chicago, June 15-16, 2001, Reported by Jules Levin). The study showed that the product is safe, and at least reduces the viral load (Sciencexpress, April 17, 2003). According to Aerztezeitung, it reduced the viral load by 99.99% in a two-day i.v. regimen in a first study with HCV-patients, without any remarkable side effects.
Vertex Pharmaceuticals plans to start a trial later this year with its hepatitis C protease inhibitor VX-950 (Pollack, A., NY Times 3/11/2003, H.I.V. Lessons Used in Hepatitis C Treatment).
Researchers have recently found a trigger, which releases IRF-3 (interferon regulatory factor 3), and were able to find the protease that blocks the IRF-3. Schering-Plough’s SCH6, a protease inhibitor, is being used for research with HCV genotype 1. It is hoped that it may make IFN treatments more effective, even with lower doses (Sciencexpress, April 17, 2003).
Idun Pharmaceuticals is designing small molecule caspase protease inhibitors to inhibit cell death in tissues and organs. Its product IDN-6556 was found safe and well tolerated in a Phase I clinical trial involving 50 adults, some with Hep C. Phase II trials will be done on HCV+ patients (PRNewswire Jan. 31, 2002, Idun Pharmaceuticals' Clinical Trial Demonstrates Safety Of Liver Disease Drug, and May 20, 2002, IDN-6556, a caspase inhibitor completes Phase 1 clinical trial for HCV).
All of the other protease inhibitors listed here are in the preclinical stage.
Abott Protease Inhibitor, Agouron Protease Inhibitor, Axys Protease Inhibitor, BILN-504 SE BILN-466 SE;
BILN-705 SE; BILN-303 SE (Peptide-based molecules that inhibit the NS3 protease of the hepatitis C virus), Corvas Protease, Hoffman-La Roche Ro-32-6167 Ro-32-6168 (
).
