There are two main areas of research into disrupting the life cycle of the virus. One is the attempt to block the working of some of its enzymes. An enzyme is a type of protein that triggers a particular chemical reaction. The other is to alter or silence the virus genetic information or RNA (ribonucleic acid). For the virus to able to reproduce or replicate it is currently known that three types of enzymes are essential. These are Protease, Helicase and Polymerase enzymes. Each has a slightly different function within the virus replication process.
1) Drugs that target HCV enzymes
a. Protease Inhibitors
Proteases play a crucial role in HCVs ability to reproduce. Once HCV gains entry into a liver cell it unravels itself releasing the instructions to build up new protein structures using its own components and those of the host cell. It is during this phase the virus passes its genetic information into the hijacked components of human cells. This extended unravelled chain is called a polypeptide. The next stage is for this chain to be chopped up or cleaved 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 cleaving. It is this cleaving that a protease inhibitor tries to stop by interfering with the function of the protease.
Protease inhibitors have been a huge breakthrough in the treatment of HIV/AIDS. However, HIV rapidly develops resistance to these drugs, which is why drugs have to be taken in powerful combinations. The risk of viral resistance is likely to pose a major challenge to the development and clinical use of protease inhibitors. Since HCV is liable to frequent mutation and adapts when it is put under pressure by the immune system it is not surprising that the virus has shown signs of resistance in the laboratory. The hope is that the development of combinations of inhibitors will combat the mutations that develop. Until a number of different protease and polymerase inhibitors are on the market, the first arrivals will be used in combination with peg-interferon/ribavirin.
Protease inhibitors potentially offer a real chance of both improving responses and shortening treatment times. At present seven or eight pharmaceutical companies are engaged in developing their own protease inhibitors.
The targets of Protease Inhibitors
The HCV protease which has had the most attention and at which most of the protease inhibitors are targeted is called NS3-4A. Not only is this protease essential for the virus to be able to replicate, it is also thought to play a part in impairing the immune response. So if it can be blocked there is the possibility of a double benefit.
b. Polymerase Inhibitors
The enzyme in HCV that controls the replication of the viruss entire genetic make-up is called HCV RNA dependent polymerase. A polymerase inhibitor tries to stop this polymerase from being able to trigger the viruss frequent mutations. It is hoped that new viral strains of the disease could then be stopped.
c. Helicase inhibitors
The HCV helicase enzyme is involved in the unwinding or unfolding of the viruss genetic structure (or RNA) structure as it prepares to mutate. There is a currently a great deal of research into ways of blocking this enzyme.
2) Drugs that target the genetic structure of HCV
RNA (ribonucleic acid) is the means by which HCV stores its genetic information. We, as humans use DNA (deoxyribonucleic acid) to store ours. A new approach to HCV treatment is to use bits of RNA or DNA to interfere with the viruss genetic structure so that it will be unable replicate or synthesize proteins. Research is also being carried out into the possibility of attempts to persuade the virus to accept new bits of genetic information into its RNA so that viral mutations will not be able to replicate.
Three main RNA based approaches in development are:
a. Antisense oligonucleotides
These are pieces of DNA or RNA molecules that can be added to the virus to stop it transferring vital genetic information throughout the virus. The main problem that has hampered research is finding a way of delivering these molecules into human circulation. They are large and difficult for the body to absorb.
b. Ribozymes
Ribozymes are enzyme-like molecules associated with RNA. Ribozymes can be modified to attach to and break other RNA molecules. The intention is that these ribozymes will act like chemical scissors to cut strands of viral RNA to stop the virus replicating and synthesising proteins.
c. RNAis
RNAi stands for RNA interference. Strands of RNA are used to interfere with or silence parts of the genetic strucutre of the virus known as messenger RNA. Messenger RNA is the template the virus uses to make proteins.
