GEN Exclusives

More »

Feature Articles

More »
Mar 15, 2009 (Vol. 29, No. 6)

Making Improvements to Standard of Care for HCV

Small Molecule Combination Therapies Are Being Investigated to Increase Response Rates

  • NS3 Helicase Inhibitors

    Dr. Boguszewska-Chachulska notes that the nonstructural protein 3 (NS3) is a highly promising target for anti-HCV therapy because of its multiple enzymatic activities, such as RNA-stimulated nucleoside triphosphatase, RNA helicase, and serine protease. The RNA helicase, the C-terminal part of NS3, is necessary for the replication of the viral RNA.

    “I am mostly focused on HCV helicase inhibitors. Our group is looking for the most active and least cytotoxic, and then analyzing thoroughly their activities, such as interactions with the helicase protein,” comments Dr. Boguszewska-Chachulska, who will discuss helicase inhibitors as potential components of a multidrug therapy against HCV at the meeting.

    Helicase inhibitors were identified by an in vitro fluorometric assay of helicase activity developed by Dr. Boguszewska-Chachulska’s team. “We subsequently demonstrated high antiviral activities in the HCV subgenomic replicon system, together with low cytotoxicity, for compounds belonging to three different groups: acridone-4-carboxylic derivatives (EC50 in the range of 9–10 uM), amidinoanthracyclines (EC50 in the range of 0.01–0.14 uM), and tropolone derivatives (EC50 corresponding to 30–46 uM),” she explains.

  • Polymerase Inhibitors

    “The HCV genome encodes a number of nonstructural proteins including the NS3 protease and the RNA-dependent RNA polymerase NS5B,” notes Dr. Smith. “The polymerase is responsible for replication of the viral genome. In the cell-based replicon assay, a model for HCV infection developed by Ralf Bartenschlager, inhibitors of both the NS3 protease and the NS5B polymerase are able to suppress viral replication. Furthermore, such inhibitors have been demonstrated clinically to reduce viral load in HCV-infected patients. These two enzymes represent important targets in the development of new therapies for the treatment of HCV.”

    Dr. Smith explains that 4´-azidocytidine (R1479) was discovered by Roche as a potent and selective inhibitor of HCV polymerase and advanced into early clinical development. R1479 appeared safe and showed modest efficacy in HCV infected persons. “However, exposure in humans was low and a prodrug of R1479 was developed. R1626, the triisobutyrate ester of R1479, entered Phase I studies in late 2004.”

    According to Dr. Smith, R1626 showed efficacy in HCV-infected patients in Phase Ib studies, and moved into Phase II combination studies with pegylated interferon and ribavirin. While the compound proved quite efficacious, with excellent reductions in viral load and increased response rates relative to SOC, there were safety issues and development was discontinued in 2008, he said. 


Add a comment

  • You must be signed in to perform this action.
    Click here to Login or Register for free.
    You will be taken back to your selected item after Login/Registration.

Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Should the CDC Director Resign?

Do you think the CDC chief should resign?