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		HCV Discovery

HCV infection remains an important public health problem throughout the world. At Genelabs we seek to leverage our hepatitis expertise and drug discovery capabilities to discover and develop improved treatments for this disease. We believe that the future of HCV therapy lies in the combination of multiple antiviral agents. Genelabs’ research efforts are directed at discovering best-in-class antivirals that will fit within this treatment strategy and allow for improved antiviral efficacy with greater safety than currently available treatments.

HCV Polymerase

As an RNA virus, HCV encodes its own RNA dependent RNA polymerase (known as NS5b) in order to replicate its genome. This viral specific enzyme is essential for viral replication. It uses single-stranded viral RNA as a template to initiate the synthesis and copying of the HCV RNA genome (human cells do not have any RNA dependent RNA polymerase function). The viral RNA is then translated by the host cells into the viral proteins which are then processed and assembled with the HCV RNA into new infectious virus particles for ultimate release from the host liver cell.

Genelabs is focusing its HCV drug discovery efforts on selectively inhibiting this viral specific target. Therapeutically, this should be an ideal target that may yield highly efficacious anti-HCV drugs. The absence of a similar human enzyme should theoretically allow potent and safe antivirals to be discovered, which may be more efficacious and better tolerated than current HCV treatments.

Visualization of the viral RNA copying process via the HCV RNA polymerase. Four different images depict the HCV RNA polymerase alone, the polymerase with a short template strand bound (yellow) and the polymerase with a growing double-stranded RNA being extruded from the active site. The domains of the “right-handed model” of the HCV RNA polymerase are shown in green (thumb), red (palm) and fingers (blue and light blue).

The structure of this enzyme follows the classic polymerase “right handed model” with areas referred to as fingers, thumb, and palm domains. While it has similarities to other polymerases, important differences have been noted for HCV’s unique structure and mechanism. From this information, a similar strategy has been initiated to that employed in the successful treatment of HIV infection.

Genelabs is currently pursuing two distinct therapeutic strategies against the HCV polymerase. These parallel and potentially complementary strategies, using different mechanisms for inhibition of the virus, utilize different chemical structures, nucleosides and non-nucleosides. Utilizing these approaches, we have identified highly potent potential drug candidates for which we have initiated preclinical studies.

HCV Screening Efforts

In addition to our discovery and development efforts against HCV polymerase, we are assaying a variety of other HCV viral targets. This diversification is intended to further leverage Genelabs’ expertise in Hepatitis C and provide additional opportunities to discover novel drugs.

HCV Life Cycle (clockwise from top left):
The HCV life cycle presents a variety of accessible targets with potential therapeutic utility. Initially, the HCV virus recognizes and is incorporated into human liver cells. The internalized virus then dissociates, liberating the viral RNA genome. The HCV RNA is then translated by the host ribosomes, producing the HCV polypeptide. This polypeptide is subsequently processed, first by host peptidases then by the HCV proteases (NS2 and NS3) into 10 different HCV proteins. The non-structural proteins (NS2-NS5b) are next assembled and localized within the liver cell to form a replication complex which produces multiple copies of the HCV RNA genome. These RNA copies are then able to reenter the life cycle, producing more HCV proteins. Eventually, the HCV structural proteins (C, E1 and E2) along with copies of the HCV RNA are packaged as infectious virus particles, released from the liver cell,
and are able to infect new cells.