Triumphs in rational drug design: Hepatitis C

English: The genome organisation of Hepatitis ...
The genome organisation of Hepatitis c virus. One open reading frame encodes a polyprotein of 3010 amino acids. This protein is cut by viral and cell enzymes to active proteins. (Photo credit: Wikipedia)

 

Despite our ever-dwindling supply of effective antibiotics, there have been a growing number of drugs that are effective against viral diseases. Many of these new drugs are not the result of happy chance or serendipity, as was penicillin, but rather the result of a process known as rational drug design.

In essence, rational drug design targets specific steps in the known biological processes of pathogens that are distinct from normal host functions. A great example of this idea are the new protease inhibitors for Hepatitis C, Boceprevir (Merck) and Telaprevir (Vertex). These agents target a specific function of the HCV serine protease (NS3/4A), rendering it non-functional. When this protease is active it shuts down the antiviral signaling and response in infected host cells1. By blocking this function the cell can once again sense HCV replication and activate multiple antiviral responses to limit and clear the infection, thereby allowing your own body to mount an effective defense against this virus.

The value of this drug for patients infected with HCV, particularly those with genotype 1, cannot be understated. Older treatment regimes were limited to Rifamprin and interferon, both of which can have side-effects and require treatment three times a week up to 48 weeks. More worryingly, the old treatment protocol was only effective for roughly 30% of people infected with HCV-1. This is significant because in the United States genotype 1 is predominant and many people who were infected had no effective treatment options. With the addition of protease inhibitors efficacy of modern HCV-1 treatment is approaching 79%2. Additionally, by adding these protease inhibitors to the treatment regiment for HCV infection it has been possible to reduce the duration of treatment from 48 weeks to 24 weeks, making patient compliance much more attainable.

The importance of this increase cannot be understated, especially since the United States has a very large proportion of the so called “Boomer” generation who are infected with this virus with very real consequences to our health care systems. It is anticipated that the long-term effects of HCV infection (such as compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver failure) will increasingly develop as this generation ages and the chronic form of the disease begins emerge.  However, a large portion of those infected with HCV have no idea that they carry the virus until they begin to develop the long-term symptoms of HCV infection, at which point much the damage is irreversible and untreatable except with liver transplants. Thankfully, this should be a final “bulge” in the diseased population, as generational lifestyle changes coupled with the screening of donated blood for HCV has greatly reduced the transmission rates of this virus and lowered the overall proportion of the population that carries this disease.

This kind of approach relies heavily upon basic science research to understand these interactions long before drugs can be designed. The Hepatitis C virus serine protease is responsible for blocking the phosphorylation and activation of interferon regulatory factor-3, a key player in innate cellular anti-viral signaling. This shutoff of interferon regulatory factor-3 allows HCV to replicate and persist in cells, effectively evading clearance. The NS3/4A protease is effectively turned off by Telaprevir and Boceprevir, both of which are peptidomimetic drugs. These drugs are small chains of amino acids designed to mimic the target peptides of NS3 and they function by occluding the active site of the NS3 protease in a way that mimics a natural substrate but cannot be process and removed, thereby inactivating the function of NS3. Once again, in order to develop these peptidomimetics the function and structure of the target enzymes must be known. This understanding requires a great deal of research but is well worth it, as the efficacy and safety of these new drugs demonstrates.

In the future we can expect to see more and more drugs designed in this manner: very specific targeting, little to no off-target effects, and a high margin of safety for patients. These drugs are a fantastic example of how basic scientific research can inform and guide highly technical and targeted drug design.

Works Cited:

1.           Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science (New York, N.Y.) 300, 1145–8 (2003).

2.            HCSP Fact Sheet from www.hcvadvocate.org

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