Potential HCV Inhibitors Target a Key Nonstructural Viral Protein

Researchers have identified a protein domain required for replication of the hepatitis C virus (HCV) and have developed a cocktail of drugs capable of inhibiting its activity.

Investigators at Stanford University (Palo Alto, CA, USA) and at Eiger BioPharmaceuticals, Inc. (Palo Alto, CA, USA) described the activity of a key domain, an amphipathic helix called 4BAH2, within a specific HCV nonstructural protein, NS4B, in a paper published in the January 20, 2010, edition of the journal Science Translational Medicine.

The investigators used a high-throughput screening system to search for small molecule drugs that could inhibit 4BAH2. They succeeded in identifying a number of first-generation small-molecule inhibitors of 4BAH2 that specifically prevented HCV replication within cells. Mechanistic studies revealed that the inhibitors targeted 4BAH2 function by preventing either 4BAH2 oligomerization or 4BAH2 membrane association.

"The discovery of a new class of HCV inhibitors against a novel target that is described in this paper paves the way for the development of novel anti-HCV strategies. This is of particular benefit because, like AIDS and tuberculosis, future effective therapy for HCV is expected to require a cocktail of several independent classes of drugs, each designed against a different viral target. As such, the types of inhibitors described in this paper represent ideal components of future anti-HCV drug cocktails," said senior author Dr. Jeffrey Glenn, associate professor of medicine, gastroenterology, and hepatology at Stanford University. "I am particularly excited to be working with the Eiger team because they have proven their ability to rapidly develop potent derivatives of the initial compounds described in my lab, and to efficiently move leads to the clinic."

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Stanford University
Eiger BioPharmaceuticals, Inc