So far the main emphasis of HCV treatment has been on targeting particular stages in the life cycle of the virus to stop it being able to replicate. There are two main areas of research in this field.
The first is concerned with drugs or therapies that try and block particular proteins on the virus. These drugs are known as protease or polymerase inhibitors. They are designed to stop the virus from being able to replicate by interfering with specific viral proteins.
The second area of research involves drugs that try to interfere with the genetic structure of the virus.
For the hepatitis C virus to be able to reproduce or replicate there are a few types of enzymes that are essential. Inhibitors are currently being researched which try to interrupt the activity of these enzymes and therefore reduce the virus’s ability to reproduce. Some of these are Protease, Polymerase, NS4B and NS5A enzymes. Each performs a slightly different function within the virus replication process.
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Structure of HCV genome
NS3 Protease Inhibitors
Proteases play a crucial role in HCVs ability to reproduce itself. Once HCV gains entry into a liver cell it releases instructions to build up new protein structures. These new structures will be made using a mixture of the virus’s components and those of the host cell. It is during this phase that the virus passes its genetic information into the hijacked human cells. This extended and unravelled chain is called a polypeptide.
The next stage is for this chain to divide into individual HCV proteins at highly specific locations. The virus can only begin to reproduce itself after all the individual HCV proteins have been cut from the polypeptide chain. It is the function of a protease to trigger this separation. A protease inhibitor tries to stop this separation happening by interfering with the function of the protease.
The HCV protease towards which most of the inhibitors are targeted is called NS3-4A. This is the protease at which the new drug Telepravir targets.
Protease inhibitors have provided a huge breakthrough in the treatment of HIV/AIDS. However, HIV rapidly develops resistance to these drugs, which is why they have to be taken in such strong combinations. The risk of viral resistance is likely to pose a major challenge to the development and clinical use of protease inhibitors.
Protease inhibitors potentially offer a real chance of both improving responses and shortening treatment times. At present 7 or 8 pharmaceutical companies are engaged in developing their own protease inhibitors.
NS5B Polymerase Inhibitors
The enzyme in HCV which controls the replication of the virus’s entire genetic make-up is called HCV RNA dependent polymerase. A polymerase inhibitor tries to stop this polymerase from being able to trigger the virus’s mutation. By doing this it is hoped that new viral strains of the disease could then be stopped.
NS4B and NS5A are two other targets that play a critical role in HCV replication and trials are currently being conducted into inhibitors.
HCV is liable to frequent mutations. When targeted by the immune system it adapts and therefore in laboratory testing the virus has shown signs of resistance.
The hope is that certain combinations of inhibitors will work to prevent the development of these mutations. Until a number of different protease and polymerase inhibitors are on the market though, the first samples will be used in combination with peg-interferon/ribavirin.