A review of the first Direct Acting Antivirals - Sofosbuvir

Viral infections treatment has always been a hard task because of viral lifecycle features. Unlike bacteria or other more complex pathogens, viruses extensively use host cell mechanisms for their replication. So, when we trying to interrupt viral replication, it will likely interrupt some of the important mechanisms of patient cells.

A great example of such a problem is the hepatitis C treatment. Until recently this disease was cured with a combination of ribavirin and interferon-alpha. The first medication causes a hemolytic anemia in most patients. This side effect occurs due to interruption of intercellular metabolism. This action has been viewed as a side effect for a long time, but recently information began to appear that such an effect can be the main mechanism of action of ribavirin [1]

Another component, interferon-alpha, also causes some unpleasant side effects. This medication acts as an immunity stimulator, activating the proliferation of human B-lymphocytes - cells that play a key role in anti-viral immunity. Also IFN-alpha stimulates the release of various cytokines - chemical compounds that stimulate inflammation. Some side effects of interferon-alpha are also related to the mechanism of action since cytokines trigger hypothalamic receptors which result in flu-like symptoms such as chills and fever [2]

As a result, some portion of patients could not get treatment due to side effects of ribavirin or IFN-alpha. A radical change occurred a few years ago when Gilead Science released a brand new drug named Sofosbuvir. The drug has a different mechanism of action that is based on interaction with a viral protein NS5B which is involved in viral RNA replication. By its nature, the drug is a nucleotide analog which means that this drug is structurally similar to natural nucleotides. But in contrast to natural components, sofosbuvir has additional charged groups which allow it to irreversibly bind to viral proteins and prevent normal nucleotides from entering the active site of the protein. At the same time, sofosbuvir can't interact with human proteins due to their higher complexity. [3]

Structures of the sofosbuvir and natural nucleotide uracil. Similar region is highlighted

And since the drug interacts only with viral proteins it doesn't affect human metabolical pathways and, therefore, doesn't cause any serious side effects.

Sofosbuvir also has two additional features. The first is that the drug interacts with a highly conservative portion of viral protein. Due to this feature, the virus can't mutate to develop resistance without decreasing the efficiency of proliferation. And even when a mutation occurs, the resistant strain of the virus is quickly replaced by more proliferation-efficient strains.

The second feature is related to the absenсe of processing of sofosbuvir by hepatic cytochrome pathways, and, therefore the interaction with other drugs. The only exсeption are some antibiotics and anti-seizure drugs which activate P-glycoprotein - a protein that is expressed in a human gut cell and affects the absorption of various drugs, including sofosbuvir [4]

Due to all of these unique features, sofosbuvir becomes one of the most effective drugs used in the treatment of viral infections. But, although almost all patients can take this treatment, in fact, for some time most of them can't do this due to a very high price of the drug. The highest price of the sofosbuvir is observed in the US, where it costs about $80,000 for the full course of treatment. Hopefully, now there are generics that are produced in India and costs about a $1,000 for a full course of treatment. The license for the production was given by the company itself with the goal of helping low-income patients.

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