Complex answer: Finding hepatitis C antivirals

Attacking hepatitis

A benzimidazole prompts the RNA of
hepatitis C to open up a portion of its
hinge-like structure and encapsulate
the inhibitor.

Hepatitis C is a chronic infectious disease that afflicts some 170 million people worldwide, causing chronic liver disease and liver cancer. Chemists at the University of California, San Diego have finally obtained the first high- resolution crystal structure of a compound that binds to the genetic material of the hepatitis C virus and blocks its replication.

Hepatitis C, according to the US Centers for Disease Control and Prevention, now kills more Americans each year than HIV/AIDS. Finding antiviral agents is thus an important quarry. Until early in 2011, with the approval of two protease inhibitors against HCV infection, there were no small molecule pharmaceuticals for attacking the virus. Indeed, the conventional therapy consisted of an immunostimulatory regimen of interferon and ribavirin, but this is not particularly effective and has several side effects. Moreover, the virus mutates rapidly with low RNA fidelity of certain enzymes from generation to generation and so there are already pre-existing drug-resistance mutations in HCV. Combination therapy with novel antiviral agents is the way forward.

Now, Thomas Hermann and colleagues Sergey Dibrov, Kejia Ding, Nicholas Brunn, Matthew Parker, Mikael Bergdahl and David Wyles at UCSD and San Diego State University, explain how the internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is "essential for the initiation of viral protein synthesis". They point out that the IRES domains adopt well-defined structures, or folds, that are could be targeted with antiviral agents that block translation. As such, the team has now determined the three-dimensional structure of the IRES subdomain IIa complexed to which is a benzimidazole translation inhibitor.

The 2.2 Å resolution structure has allowed the team to compare the unbound RNA in conjunction with solutions studies of the inhibitor bound to the target and so reveal that the ligand causes the RNA to undergo a dramatic conformational change. This adaptation leads to the formation of a deep pocket resembling the substrate binding sites in riboswitches, the team explains. "The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance," the team explains.

Lethal inhibitions

Hermann and colleagues describe details of the complex structure in the journal Proceedings of the National Academy of Sciences and suggest that the research could provide a useful model for the design of pharmaceuticals to inhibit hepatitis C virus. This is a particularly critical avenue of investigation as there are currently no available vaccines against this potentially lethal virus.

"The lack of detailed information on how inhibitors lock onto the viral genome target has hampered the development of better drugs," explains Hermann. "This structure will guide approaches to rationally design better drug candidates and improve the known benzimidazole inhibitors," he adds. "Also, the crystal structure demonstrates that the binding pocket for the inhibitors in the hepatitis C virus RNA resembles drug-binding pockets in proteins." This, Hermann points out, is an important aspect of the research as it could help scientists to overcome the perceived notion that RNA targets are too unlike traditional protein targets to be a useful focus for the discovery of small molecule inhibitors.

The discovery of a deep solvent-excluding inhibitor binding pocket in the highly conserved subdomain IIa of the HCV IRES adds, what the team refers to as "a unique dimension to the repertoire of targets for anti-HCV therapy". The architecture of the well-defined benzimidazole binding site will be a valuable starting point for the structure-based design of HCV inhibitors, supported by the notion of viral translation as an attractive therapeutic target," the team concludes.